WO2017009258A1 - Conjugués anticorps-médicament spécifiques d'axl pour le traitement du cancer - Google Patents
Conjugués anticorps-médicament spécifiques d'axl pour le traitement du cancer Download PDFInfo
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Classifications
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- C07K2317/00—Immunoglobulins specific features
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- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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Definitions
- the present invention relates to antibody-drug conjugates (ADCs) binding to human AXL for therapeutic use, particularly for treatment of resistant or refractory cancers.
- ADCs antibody-drug conjugates
- AXL is a 104-140 kDa transmembrane protein which belongs to the TAM subfamily of mammalian Receptor Tyrosine Kinases (RTKs) and which has transforming abilities (Paccez et al., 2014).
- the AXL extracellular domain is composed of a combination of two membrane-distal N- terminal immunoglobulin (Ig)-like domains (Igl and Ig2 domains) and two membrane-proximal fibronectin type III (FNIII) repeats (the FN1- and FN2-domains) (Paccez et al., 2014).
- AXL Enhanced or de novo expression of AXL has been reported in a variety of cancers, including gastric, prostate, ovarian, and lung cancer (Paccez et al., 2014).
- gastric, prostate, ovarian, and lung cancer Paccez et al., 2014.
- tyrosine kinase inhibitors include tyrosine kinase inhibitors, serine/threonine kinase inhibitors and/or chemotherapy.
- tumor cells with resistance to Epidermal Growth Factor Receptor (EGFR) targeted therapy (Wilson et al., 2014; Brand et al., 2015; Zhang et al., 2012; Blakely et al., 2012) or inhibitors of the B-raf (BRAF) pathway (Muller et al., 2014) showed enhanced or de novo AXL expression.
- EGFR Epidermal Growth Factor Receptor
- AXL expression was also induced in prostate cancer cells wit h acq u ired resistance to m etform in ( Bansal et al. , 201 5) .
- AXL can be activated upon binding of its ligand, the vitamin K-dependent growth arrest-specific factor 6 (Gas6). Gas6-binding to AXL leads to AXL dimerization, autophosphorylation and subsequent activation of intracellular signaling pathways, such as the PI3K/AKT, mitogen- activated protein kinase (MAPK), STAT and NF- ⁇ cascades (Leconet et al., 2013). In cancer cells, AXL expression has been associated with tumor cell motility, invasion, migration, and is involved in epithelial-to-mesenchymal transition (EMT) (Linger et al., 2010).
- EMT epithelial-to-mesenchymal transition
- Targeted inhibition of AXL and/or its ligand Gas6 may be effective as anti-tumor therapy using, e.g., small molecules or anti-AXL antibodies (Linger et al., 2010).
- Anti-AXL antibodies have been described that attenuate NSCLC and breast cancer xenograft growth in vivo by downregulation of receptor expression, reducing tumor cell proliferation and inducing apoptosis (Li et al., 2009; Ye et al., 2010; WO 2011/159980, Genentech).
- Various other anti-AXL antibodies have also been reported (Leconet et al., 2013; lida et al., 2014; WO 2012/175691, INSE M; WO
- ADCs based on anti-AXL antibodies can be used to efficiently treat cancers which are resistant, or which have a high tendency to become resistant, to certain therapeutic agents.
- the invention relates to an ADC comprising an antibody binding to human AXL for use in treating cancer resistant to at least one therapeutic agent selected from the group consisting of a tyrosine kinase inhibitor, a PI3K inhibitor, an antagonistic antibody binding to a receptor tyrosine kinase, a serine/threonine kinase inhibitor and a chemotherapeutic agent.
- a therapeutic agent selected from the group consisting of a tyrosine kinase inhibitor, a PI3K inhibitor, an antagonistic antibody binding to a receptor tyrosine kinase, a serine/threonine kinase inhibitor and a chemotherapeutic agent.
- the invention relates to an ADC comprising an antibody binding to human AXL, for use in treating a cancer in combination with a therapeutic agent selected from a chemotherapeutic agent, a tyrosine kinase inhibitor, a PI3K inhibitor, an antagonistic antibody binding to a receptor tyrosine kinase, or a serine/threonine kinase inhibitor.
- a therapeutic agent selected from a chemotherapeutic agent, a tyrosine kinase inhibitor, a PI3K inhibitor, an antagonistic antibody binding to a receptor tyrosine kinase, or a serine/threonine kinase inhibitor.
- the ADC and therapeutic agent may, for example, be administered simultaneously, separately or sequentially.
- Figure 1 Binding curves of anti-AXL antibodies to HEK293 cells transfected with (A) human AXL-ECD, (B) cynomolgus AXL-ECD, or (C) mouse AXL-ECD. Data shown are mean fluorescence intensities (MFI) of one representative experiment, as described in Example 2.
- FIG. 2 Binding of anti-AXL antibodies to mouse-human AXL chimeras was performed as described in Example 3. The following Homo sapiens AXL (hsAXL) and Mus musculus AXL (mmAXL) chimeric proteins were tested: (A) hsAXL and mock, (B) hsAXL-mmECD, (C) hsAXL- mmlgl, (D) hsAXL-mmlg2, (E) hsAXL-mmFNl, (F) hsAXL-mmFN2.
- hsAXL Homo sapiens AXL
- mmAXL Mus musculus AXL
- FIG. 3 Anti-AXL antibody-dependent cell-mediated cytotoxicity in A431 cells. Antibody-dependent cell-mediated cytotoxicity by anti-AXL antibodies in A431 cells was determined as described in Example 4.
- FIG. 4 Binding characteristics of AXL antibody-drug conjugates (AXL-ADCs). Binding of AXL-ADCs on HEK293T cells transiently transfected with human AXL was determined as described in Example 5. Data shown are mean fluorescence intensities (MFI) of one representative experiment.
- Figure 5 In vitro cytotoxicity induced by AXL antibody-drug conjugates. Induction of cytotoxicity by AXL antibody-drug conjugates was determined as explained in Example 6.
- FIG. 6 Antibody VH and VL variants that allow binding to AXL. Antibodies with identical VL or VH regions were aligned and differences in VH ( Figures A-D) or VL ( Figure E) sequences, respectively, were identified and indicated by boxes in the figures. CDR regions are underlined.
- Figure 8 Anti-tumor activity by MMAE-conjugated AXL antibodies in a therapeutic LCLC-103H xenograft model as described in Example 9.
- Figure 9 Immunohistochemical staining of frozen PAXF1657 tumor sections (pancreas cancer PDX model) using a pool of AXL monoclonal antibodies as described in Example 10.
- Figure 10 Average tumor size after therapeutic treatment with AXL-ADCs the PAXF1657 model.
- An unconjugated AXL Humab (C) and an untargeted ADC (D) do not show antitumor activity, indicating that the therapeutic capacity of AXL-ADCs was dependent on the cytotoxic activity of MMAE and on target binding, error bars represent S.E.M.
- Figure 11 Binding of anti-AXL antibodies to mouse-human AXL chimeras was performed as described in Example 11. The following Homo sapiens AXL (hsAXL) and Mus musculus AXL (mmAXL) chimeric proteins were tested: (A) hsAXL and mock, (B) hsAXL-mmECD, (C) hsAXL- mmlgl, (D) hsAXL-mmlg2, (E) hsAXL-mmFNl, (F) hsAXL-mmFN2.
- hsAXL Homo sapiens AXL
- mmAXL Mus musculus AXL
- FIG. 12 Binding of human Gas6 (hGas6) on A431 cells that had been pre-incubated with antibodies binding to the Igl domain of AXL. Data shown are mean fluorescence intensities (MFI) of one representative experiment.
- Figure 13 Anti-tumor activity of MMAE-conjugated AXL antibodies in a therapeutic A431 xenograft model, that produces high levels of endogeneous Gas6, as described in Example 13. Panels A and B show results from 2 independent experiments.
- Figure 14 Anti-tumor activity of MMAE-conjugated AXL antibodies in a therapeutic LCLC-103H xenograft model, that expresses low levels of endogenous Gas6, as described in Example 13. Panels A and B show results from 2 independent experiments.
- Figure 15 Induction of cytotoxicity by AXL-ADCs in A431 cells (A) and MDA-MB231 cells (B) was determined as described in Example 8.
- FIG. 16 AXL staining in thyroid, esophageal, ovarian, breast, lung, pancreatic, cervical and endometrial cancer.
- the average AXL staining intensity (OD) of AXL-positive cells is plotted on the X-axis, and the percentage of AXL-positive tumor cells is plotted on the Y-axis.
- Each dot represents a tumor core, derived from an individual patent.
- Figure 17 Representative examples of AXL-immunostained tumor cores for different tumor indication.
- FIG. 18 AXL antibodies specifically bind AXL but not to other TAM receptor family members. Binding of HuMab-AXL antibodies to HEK293 cells transfected with human AXL (A), human MER (B), human TYR03 (C), or untransfected HEK293 cells (D). To confirm proper expression of transfected cells, untransfected HEK293F cells and cells transfected with AXL (E), MER (F), or TYR03 (G) were stained with MER- and TYR03-specific antibodies. Data shown are mean fluorescence intensities (MFI) of one representative experiment, as described in Example 15.
- MFI mean fluorescence intensities
- FIG. 19 Detection of AXL antibodies on the plasma membrane of tumor cell lines that had been incubated with AXL-antibodies for 1 hour at 4°C, followed by an overnight incubation 4°C or 37°C.
- AXL-antibodies for 1 hour at 4°C, followed by an overnight incubation 4°C or 37°C.
- C and D Calu-1 cells
- FIG 20 Geomean fluorescence intensity of LCLC-103H cells after incubation with AXL antibodies that had been complexed to Fab-TAMRA/QSY7. lgGl-bl2 and Fab-TAMRA/QSY7 alone were included as negative controls.
- Figure 21 (A) Average tumor size after therapeutic treatment with lgGl-AXL-107- vcMMAE in the esophageal cancer PDX model ES0195. lgGl-bl2 and lgGl-bl2-MMAE were included as isotype control antibody and isotype control ADC, respectively.
- B Tumor size in individual mice on day 32 after injection of MDA-MB-231-luc D3H2LN tumor cells in the mammary fat pads of female SCID mice. * p ⁇ 0.05; ** p ⁇ 0.0001
- FIG. 22 Therapeutic effect of AXL-ADCs in a patient-derived cervical cancer xenograft model.
- A Average tumor size after therapeutic treatment with lgGl-AXL-183-vcMMAE or lgGl-AXL-726-vcMMAE in the cervical cancer PDX model CEXF 773.
- lgGl-bl2 and lgGl-bl2-MMAE were included as isotype control antibody and isotype control ADC, respectively.
- B Tumor size in individual mice on day 28 after initiation of treatment in the cervical cancer PDX model CEXF 773. * p ⁇ 0.001.
- FIG. 23 Therapeutic activity of AXL-ADCs in an orthotopic breast cancer xenograft model.
- A Average tumor size after therapeutic treatment with lgGl-AXL-183-vcMMAE or IgGl-AXL-
- FIG. 24 Cytotoxicity of lgGl-AXL-107-vcMMAE in human tumor cell lines with different levels of AXL expression on the plasma membrane.
- AXL expression in the plasma membrane of human tumor cell lines was assessed using Qifikit analysis, and the cytotoxicity of lgGl-AXL-107-vcMMAE was expressed as the percentage of viable tumor cells that remained in the cell cultures after exposure to 1 ⁇ g/mL lgGl-AXL-107-vcMMAE.
- Figure 25 Improved anti-tumor efficacy of lgGl-AXL-107-vcMMAE in an erlotinib- resistant NSCLC patient-derived xenograft (PDX) model in combination with erlotinib.
- lgGl-bl2 and lgGl-bl2-MMAE were included as isotype control antibody and isotype control ADC, respectively. *, p ⁇ 0.05; **, p ⁇ 0.01; ns, not significant (one-way ANOVA test).
- FIG 26 Enhanced Axl protein expression in NSCLC cell lines with acquired resistance to EGF -TKIs.
- the expression of Axl protein was determined by Western blotting. Actin staining was used as control for equal protein loading. Expression of Axl was evaluated in cells that had been cultured in the presence (+) or absence (-) of erlotinib.
- Figure 27 Sensitivity of parental (wild-type) and eriotinib-resistant HCC827 and PC9 cells to lgGl-AXL-107-vcMMAE (A, B, F, G, H, J, K) or EGF -TKIs (C, D, E, and I) was evaluated in viability assays.
- FIG. 28 AXL expression in established melanoma cell lines and patient-derived low passage primary melanoma lines (PDX).
- A Variable levels of AXL expression were observed in established melanoma cell lines. Enhanced or de novo AXL expression was observed in PLX4720 resistant cell lines (A375-R, SKMEL28R, SKMEL147).
- B AXL expression was observed in 8/15 patient derived primary melanoma lines. In both established melanoma cell lines and low passage PDX cultures, AXL expression was inversely correlated with MITF expression.
- Figure 29 AXL protein expression on the cell surface. Examples of AXL expression as determined by quantitative flow cytometry in an Axl-negative and an Axl-positive melanoma cell line. The light gray plots represent staining with AXL-specific antibodies, while the dark grey plots represent staining with isotype control antibody.
- FIG. 30 Sensitivity of established melanoma cell lines to lgGl-AXL-107-vcMMAE.
- Melanoma cell lines (A-F; CDX) were treated with lgGl-AXL-107-vcMMAE or the isotype control ADC lgGl-bl2-vcMMAE for 5 days in triplicate.
- Cell viability was assessed with a CellTiter-Glo assay and plotted against the ADC concentration.
- Figure 31 Sensitivity of primary melanoma cell cultures to lgGl-AXL-107-vcMMAE.
- Low passage primary melanoma cell lines (A-C; PDX) were treated with lgGl-AXL-107-vcMMAE or the isotype control ADC lgGl-bl2-vcMMAE for 8 days in triplicate. Cell viability was assessed with a CellTiter-Glo assay and plotted against the ADC concentration.
- FIG. 32 Anti-tumor efficacy of lgGl-AXL-107-vcMMAE in the eriotinib-resistant LU0858 NSCLC patient-derived xenograft (PDX) model. Average tumor size after therapeutic treatment with lgGl-AXL-107-vcMMAE, eriotinib, or eriotinib in combination with lgGl-AXL-107- vcMMAE is shown (A). lgGl-bl2 and lgGl-bl2-MMAE were included as isotype control antibody and isotype control ADC, respectively.
- FIG. 33 Anti-tumor efficacy of lgGl-AXL-107-vcMMAE in the eriotinib-resistant LU1868 NSCLC patient-derived xenograft (PDX) model. Average tumor size after therapeutic treatment with lgGl-AXL-107-vcMMAE, eriotinib, or eriotinib in combination with lgGl-AXL-107- vcMMAE is shown (A). lgGl-bl2 and lgGl-bl2-MMAE were included as isotype control antibody and isotype control ADC, respectively.
- LXFA 526 NSCLC patient-derived xenograft (PDX) model LXFA 526 NSCLC patient-derived xenograft (PDX) model.
- A Average tumor size after therapeutic treatment with lgGl-AXL-107-vcMMAE, eriotinib, or eriotinib in combination with lgGl-AXL-107- vcMMAE is shown.
- B Mean tumor size and SEM of each group per time point and tumor size per individual mouse per group on day 23. *, p ⁇ 0.05; **, p ⁇ 0.01; ns, not significant (Mann-Whitney test).
- FIG. 35 Anti-tumor efficacy of lgGl-AXL-107-vcMMAE in the NSCLC patient-derived xenograft (PDX) model LXFA 677 (A) and LXFA 677_3 (C), which has acquired resistance to eriotinib. Average tumor size after therapeutic treatment with lgGl-AXL-107-vcMMAE, eriotinib, or eriotinib in combination with lgGl-AXL-107-vcMMAE is shown.
- PDX NSCLC patient-derived xenograft
- (B, D) Mean tumor size and SEM of each group per time point and tumor size per individual mouse per group on day 21 of the LXFA 677 model (B) or on day 37 of the LXFA 677_3 model (D). *, p ⁇ 0.05; **, p ⁇ 0.01; ns, not significant (Mann-Whitney test).
- FIG. 36 Anti-tumor efficacy of lgGl-AXL-107-vcMMAE in the melanoma model SKMEL147.
- Average tumor size after therapeutic treatment with lgGl-bl2, lgGl-bl2-vcMMAE, IgGl- AXL-107, or lgGl-AXL-107-vcMMAE is shown (A).
- FIG. 37 SKMEL28 wild-type cells (red) and PLX4720-resistant SKMEL28- cells (green) were mixed 1:1 and treated with lgGl-AXL-107-vcMMAE (AXL-ADC), lgGl-bl2-MMAE (bl2- ADC), PLX4720 (PLX), dabrafenib (dabr), trametinib (tram), or combinations as indicated.
- A Total cell numbers relative to untreated cells.
- B GFP/mCherry ratio corresponding to the ratio SKMEL28- R/SKMEL28 cells.
- FIG. 38 Anti-tumor efficacy of lgGl-AXL-107-vcMMAE in the cervical cancer PDX model CV1664.
- A Average tumor size after therapeutic treatment with lgGl-bl2, lgGl-bl2- vcMMAE, lgGl-AXL-107, lgGl-AXL-107-vcMMAE, or paclitaxel is shown.
- B Mean tumor size and SEM of each group per time point and tumor size per individual mouse per group on day 46 is shown.
- A Example of melanoma with positive +++ Axl staining intensity
- B Example of melanoma with positive Axl staining intensity between + and ++
- D Example of heterogeneous Axl expression with ++ intensity within primary melanoma tissue.
- AXL-specific ADCs also referred to as "AXL-ADCs" herein
- AXL-ADCs as defined in any aspect or embodiment herein, for use in treating cancers or tumors which are resistant, or which have a high tendency to become resistant, to certain chemotherapeutics, tyrosine kinase inhibitors (e.g., EGFR inhibitors), serine/threonine kinase inhibitors (e.g., BRAF inhibitors), PI3K inhibitors and antagonistic antibodies to receptor tyrosine kinases, as described herein.
- tyrosine kinase inhibitors e.g., EGFR inhibitors
- serine/threonine kinase inhibitors e.g., BRAF inhibitors
- PI3K inhibitors PI3K inhibitors
- antagonistic antibodies to receptor tyrosine kinases as described herein.
- the present invention is based, at least in part, on the discovery that AXL-ADCs are effective both in vitro and in vivo in inducing cytotoxicity in tumor cells resistant to EGFR targeted therapy, BRAF/MEK-targeted therapy or microtubule-targeting agents.
- AXL-ADCs are effective both in vitro and in vivo in inducing cytotoxicity in tumor cells resistant to EGFR targeted therapy, BRAF/MEK-targeted therapy or microtubule-targeting agents.
- NSCLC cells with acquired resistance to the EGFR inhibitors eriotinib, gefitinib and afatinib showed reduced viability upon treatment with AXL-ADC (Example 21), and eriotinib-resistant models with different EGFR gene status showed sensitivity for AXL-ADC (Example 22; Table 17).
- treatment with the EGFR inhibitor eriotinib did not induce anti-tumor activity
- treatment with AXL-ADC or a combination of AXL-ADC and eriotinib induced potent anti-tumor activity (Example 22).
- an eriotinib-resistant cell-line derived from an erlotinib-sensitive cell-line was particularly sensitive to AXL-ADC - a stronger anti-tumor activity was obtained at a lower dose (Example 22).
- melanoma cell lines resistant to the BRAF-inhibitors PLX4720 (an analog of vemurafenib) or dabrafenib showed enhanced expression of AXL and were sensitive to treatment with AXL-ADC, and AXL-ADC showed strong anti-tumor activity in an in vivo melanoma model resistant to PLX4720 (Example 23).
- AXL-ADC induced complete or partial tumor regression in a tumor model of cervical cancer where tumors had progressed after treatment with paclitaxel (Example 24).
- the invention provides an AXL-ADC, e.g., HuMax-AXL-ADC, for use in treating cancer resistant and/or having a high tendency to become resistant to at least one therapeutic agent selected from the group consisting of a tyrosine kinase inhibitor, a PI3K inhibitor, an antagonistic antibody to a receptor tyrosine kinase, a serine/threonine kinase inhibitor and a chemotherapeutic agent.
- the therapeutic agent is selected from a tyrosine kinase inhibitor, a serine/threonine kinase inhibitor and a chemotherapeutic agent.
- the invention provides an AXL-ADC, e.g., HuMax-AXL-ADC, for use in treating a cancer in combination with a therapeutic agent selected from a chemotherapeutic agent, a tyrosine kinase inhibitor, a PI3K inhibitor, an antagonistic antibody to a receptor tyrosine kinase, and a serine/threonine kinase inhibitor, wherein the ADC and therapeutic agent are administered simultaneously, separately or sequentially.
- the cancer may be resistant to the therapeutic agent and/or may have a high tendency to become resistant to the therapeutic agent.
- the therapeutic agent is selected from a tyrosine kinase inhibitor, a serine/threonine kinase inhibitor and a chemotherapeutic agent.
- a “resistant”, “treatment-resistant” or “refractory” cancer, tumor or the like means a cancer or tumor in a subject, wherein the cancer or tumor did not respond to treatment with a therapeutic agent from the onset of the treatment (herein referred to as “native resistance”) or initially responded to treatment with the therapeutic agent but became non- responsive or less responsive to the therapeutic agent after a certain period of treatment (herein referred to as “acquired resistance”), resulting in progressive disease.
- acquired resistance for solid tumors, also an initial stabilization of disease represents an initial response.
- Other indicators of resistance include recurrence of a cancer, increase of tumor burden, newly identified metastases or the like, despite treatment with the therapeutic agent.
- Whether a tumor or cancer is, or has a high tendency of becoming, resistant to a therapeutic agent can be determined by a person of skill in the art.
- NCCN National Comprehensive Cancer Network
- ESMO European Society for Medical Oncology
- ESMO European Society for Medical Oncology
- cancers or tumors developing resistance to certain chemotherapeutics e.g., microtubule-targeting agents ("MTAs") such as taxanes
- MTAs microtubule-targeting agents
- tyrosine kinase inhibitors e.g., EGF inhibitors
- serine/threonine kinase inhibitors e.g., BRAF- or MEK-inhibitors
- PI3K inhibitors e.g., BRAF- or MEK-inhibitors
- the term "subject” is typically a human to whom the AXL-ADC is administered, including for instance human patients diagnosed as having a cancer that may be treated by killing of AXL-expressing cells, directly or indirectly.
- a cancer which "has a high tendency" for resistance to a specific therapeutic agent is a cancer which is known to be associated with a high tendency of being or becoming resistant or refractory to treatment with a certain class of drugs.
- a cancer patient who is being treated or who has been found to eligible for treatment with a therapeutic agent as described herein for which there is a correlation between resistance and enhanced or de novo expression of AXL suffers from a cancer having a high tendency for resistance.
- Non-limiting examples of cancers and therapeutic agents known to be associated with enhanced or de novo expression of AXL and which are thus may have a high tendency to become resistant to the therapeutic agent are shown in Table 1 below.
- AXL-ADC induced complete or partial tumor regression in a tumor model of cervical cancer where tumors had progressed after treatment with paclitaxel.
- Other cancers and tumor types with native or acquired resistance to a therapeutic agent and sensitive to AXL-ADC treatment are also described elsewhere herein.
- TKI tyrosine-kinase inhibitor
- TKI tyrosine-kinase inhibitor
- a compound typically a pharmaceutical, which inhibits tyrosine kinases or down-stream signaling from tyrosine kinases.
- Tyrosine kinases are enzymes responsible for the addition of a phosphate group to a tyrosine of a protein (phosphorylation), a step that TKIs inhibit, either directly or indirectly.
- TKIs are useful for cancer therapy.
- TKIs and their targets are shown in Table 1 above, and include, e.g., EGFR inhibitors such as erlotinib.
- EGFR inhibitors such as erlotinib.
- tyrosine kinase in h ibitor refer to com pou nds wh ich specif ically inhibit the protein phosphorylation activity of a tyrosine kinase, e.g., the tyrosine kinase activity of the EGFR. While many TKIs in clinical use are small molecule pharmaceuticals, there are also
- rTKIs receptor tyrosine kinase inhibitors
- mAb/rTKIs antagonistic antibodies which bind to the extracellular portion of a receptor tyrosine kinase
- a " phosphoinosit ide 3- kinase inh ibitor" or " PI 3KI” as used herein refers to a com pound , typically a pharm aceut ical, wh ich in h ibits an enzym e in the PI 3K/AKT pathway. Exam ples of PI 3Kl s include Alpelisib ( BYL791 ) .
- Serine/threonine kinases are enzymes responsible for the phosphorylation of the hydroxyl-group of a serine or threonine residue, a step that S/Th KIs inhibit, either directly or indirectly. Phosphorylation of serines or threonines results in the activation of intracellular signal transduction cascades.
- S/Th KIs useful for cancer therapy examples include BRAF-inhibitors such as vemurafenib and analogs or derivatives thereof.
- BRAF-inhibitors such as vemurafenib and analogs or derivatives thereof.
- serine/threonine kinase inhibitor refer to compounds which specifically inhibit the protein phosphorylation activity of a serine/threonine kinase, e.g., the serine/threonine kinase activity of a mutant BRAF or MEK.
- Vemurafenib (PLX4032) is an orally bioavailable, ATP-competitive, small-molecule inhibitor of mutated BRAF kinase, which selectively binds to and inhibits BRAF comprising certain mutations, resulting in an inhibition of an over-activated MAPK signaling pathway downstream in the mutant BRAF kinase-expressing tumor cells.
- BRAF mutations identified in human cancers are generally located in the glycine-rich P loop of the N lobe and the activation segment and flanking regions within the kinase domain.
- Vemurafenib binds to and inhibits BRAF kinase having certain of these mutations, such as, but not limited to, an amino acid substitution in residue V600 [e.g., V600E), residue L597 [e.g., L597R; Bahadoran et al., 2013); and residue K601 (Dahlman et al., 2012).
- a “derivative" of a drug is a compound that is derived or derivable, by a direct chemical reaction, from the drug.
- an “analog” or “structural analog” of a drug is a compound having a similar structure and/or mechanism of action to the drug but differing in at least one structural element.
- “Therapeutically active” analogs or derivatives of a drug such as, e.g., vemurafenib or erlotinib, have a similar or improved therapeutic efficacy as compared to the drug but may differ in, e.g., one or more of stability, target specificity, solubility, toxicity, and the like.
- Tables 2 and 3 below show BRAF and EGFR inhibitors which have a similar mechanism of action (BRAF or EGFR inhibition, respectively) as vemurafenib and erlotinib, respectively.
- melanoma resistance to vemurafenib, dabrafenib, trametinib or combinations of any two or more thereof; and NSCLC resistance to eriotinib, gefitinib or afatinib, or combinations of any two or more thereof, may be associated with de novo or enhanced expression of AXL by the tumor cells.
- tumors may be eligible for treatment with an AXL-specific ADC.
- the invention provides a method of treating a cancer in a subject, wherein the cancer is resistant to at least one therapeutic agent selected from a tyrosine kinase inhibitor, a serine/threonine kinase inhibitor, and a chemotherapeutic agent, the method comprising administering an AXL-ADC.
- the cancer may for example, have acquired the resistance during a previous or still on-going treatment with the therapeutic agent. Alternatively, the cancer was resistant from the onset of treatment with the therapeutic agent.
- the cancer is an AXL-expressing cancer.
- the therapeutic agent is a PI3K inhibitor or a mAb/rTKI.
- the invention provides a method of treating a cancer in a subject, the method comprising administering an AXL-ADC in combination with at least one therapeutic agent selected from a chemotherapeutic agent, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, wherein the ADC and therapeutic agent are administered simultaneously, separately or sequentially.
- the cancer has a high tendency for resistance to the therapeutic agent.
- the cancer is resistant to the therapeutic agent.
- the therapeutic agent is a PI3K inhibitor or a mAb/rTKI.
- cancers may include, but are not limited to, melanoma, non-small cell lung cancer (NSCLC), cervical cancer, ovarian cancer, squamous cell carcinoma of the head and neck (SCCHN), breast cancer, gastrointestinal stromal tumors (GISTs), renal cancer, neuroblastoma, esophageal cancer, rhabdomyosarcoma, acute myeloid leukaemia (AML), an chronic myeloid leukaemia (CML).
- NSCLC non-small cell lung cancer
- SCCHN squamous cell carcinoma of the head and neck
- GISTs gastrointestinal stromal tumors
- renal cancer neuroblastoma
- esophageal cancer rhabdomyosarcoma
- AML acute myeloid leukaemia
- CML chronic myeloid leukaemia
- the cancer or tumor is selected from cervical cancer, melanoma, NSCLC, SCCHN, breast cancer, GIST, renal cancer, neuroblastoma, esophageal cancer and rhabdomyosarcoma.
- the cancer is a hematological cancer selected from AML and CML.
- the cancer or tumor is characterized by at least one mutation in the EGF amino acid sequence selected from L858R and T790M, such as e.g., L858R or T790M/L858R.
- the cancer or tumor may be an NSCLC.
- the at least one therapeutic agent consists of or comprises a TKI inhibitor which is an EGFR antagonist, a HER2 antagonist, an ALK-inhibitor, a FLT3 inhibitor, or a combination of two or more thereof.
- TKIs include erlotinib, gefitinib, lapatinib, osimertinib, rociletinib, imatinib, sunitinib, afanitib, crizotinib, midostaurin (PKC412) and quizartinib (AC220).
- the TKI is an EGFR inhibitor, such as erlotinib or a therapeutically active analog or derivative thereof, e.g., afatinib, lapatinib, osimertinib, rociletinib, or gefitinib.
- the tyrosine kinase inhibitor is eriotinib and the cancer is an NSCLC, resistant to or having a high tendency for becoming resistant to eriotinib.
- the tyrosine kinase inhibitor is eriotinib and the cancer is a pancreatic cancer, resistant to or having a high tendency for becoming resistant to eriotinib.
- the tyrosine kinase inhibitor is gefitinib and the cancer is an NSCLC, resistant to or having a high tendency for becoming resistant to gefitinib.
- the tyrosine kinase inhibitor is crizotinib and the cancer is a NSCLC, resistant to or having a high tendency for becoming resistant to crizotinib.
- the tyrosine kinase inhibitor is lapatinib and the cancer is a breast cancer, resistant to or having a high tendency for becoming resistant to lapatinib.
- the tyrosine kinase inhibitor is imatinib and the cancer is a CML, resistant to or having a high tendency for becoming resistant to imatinib.
- the tyrosine kinase inhibitor is imatinib and the cancer is a GIST, resistant to or having a high tendency for becoming resistant to imatinib.
- the tyrosine kinase inhibitor is sunitinib and the cancer is a GIST, resistant to or having a high tendency for becoming resistant to sunitinib.
- the tyrosine kinase inhibitor is sunitinib and the cancer is a renal cancer, resistant to or having a high tendency for becoming resistant to sunitinib.
- the tyrosine kinase inhibitor is crizotinib and the cancer is a neuroblastoma, resistant to or having a high tendency for becoming resistant to crizotinib.
- the tyrosine kinase inhibitor is midostaurin (PKC412) and the cancer is AML, resistant to or having a high tendency for becoming resistant to midostaurin.
- the tyrosine kinase inhibitor is quizartinib and the cancer is an AML resistant to or having a high tendency for becoming resistant to quizartinib.
- tyrosine kinase inhibitor is afatinib and the cancer is a breast cancer, resistant to or having a high tendency for becoming resistant to afatinib.
- tyrosine kinase inhibitor is axitinib and the cancer is a renal cancer, resistant to or having a high tendency for becoming resistant to axitinib.
- tyrosine kinase inhibitor is lenvatinib and the cancer is a thyroid cancer, resistant to or having a high tendency for becoming resistant to lenvatinib.
- the tyrosine kinase inhibitor is an EGFR-inhibiting agent, such as, e.g., erlotinib or a therapeutically active analog or derivative thereof, preferably wherein the cancer is an NSCLC, resistant to or having a high tendency for becoming resistant to the EGFR-inhibiting agent.
- the cancer or tumor e.g., the NSCLC
- the cancer or tumor is characterized by at least one mutation in the EGFR selected from L858R and T790M, or a combination thereof.
- the at least one therapeutic agent consists of or comprises a PI3K inhibitor.
- PI3K inhibitors include alpelisib and therapeutically active analogs and derivatives thereof.
- the ⁇ 3 ⁇ is alpelisib (BYL719) and the cancer is a SCCHN, resistant to or having a high tendency for becoming resistant to alpelisib.
- the at least one therapeutic agent consists of or comprises an antagonistic antibody which binds to the extracellular portion of a receptor tyrosine kinase.
- mAb/rTKIs include cetuximab and anti-IGF-IR MAB391 as well as therapeutically active analogs or derivatives of cetuximab and MAB391.
- the mAb/rTKI is cetuximab and the cancer is a SCCHN, resistant to or having a high tendency for becoming resistant to cetuximab.
- the mAb/rTKI is anti-IGF-IR antibody MAB391 and the cancer is an SCCHN, resistant to or having a high tendency for becoming resistant to MAB391.
- the at least one therapeutic agent consists of or comprises a S/Th Kl which is a BRAF-inhibitor, MEK-inhibitor or a combination thereof.
- the S/Th Kl is a BRAF-inhibitor, such as vemurafenib (PLX4032) or a therapeutically effective derivative or analog thereof, e.g., PLX4720 or dabrafenib; or VTXKIIE.
- the S/Th Kl is a MEK- inhibitor, such as selumetinib (AZD6244) or trametinib.
- the S/Th Kl is vemurafenib and the cancer is a melanoma, resistant to or having a high tendency for becoming resistant to vemurafenib.
- the S/Th Kl is vemurafenib and the cancer is a colorectal cancer, resistant to or having a high tendency for becoming resistant to vemurafenib.
- the s/Th Kl is dabrafenib and the cancer is a melanoma, resistant to or having a high tendency for becoming resistant to dabrafenib.
- the S/Th Kl is dabrafenib and the cancer is a colorectal cancer, resistant to or having a high tendency for becoming resistant to dabrafenib.
- the S/Th Kl is selumetinib and the cancer is a pancreatic cancer, resistant to or having a high tendency for becoming resistant to selumetinib.
- the S/Th Kl is selumetinib and the cancer is a melanoma, resistant to or having a high tendency for becoming resistant to selumetinib.
- the S/Th Kl inhibitor is trametinib and the tumor is a melanoma, resistant to or having a high tendency for becoming resistant to trametinib.
- the S/Th Kl is VTXKI IE and the cancer is a melanoma, resistant to or having a high tendency for becoming resistant to VTXKII E.
- the S/Th Kl is PLX4720 and the cancer is a melanoma, resistant to or having a high tendency for becoming resistant to PLX4720.
- the at least one therapeutic agent consists of or comprises a BRAF inhibitor.
- the BRAF inhibitor is vemurafenib (PLX4032) or a therapeutically effective analog or derivative thereof, such as dabrafenib or PLX4720.
- the BRAF inhibitor is vemurafenib or a therapeutically active derivative or analog thereof, and the tumor is a melanoma resistant to or having a high tendency for becoming resistant to vemurafenib.
- Vemurafenib is an inhibitor of BRAF kinase harboring certain mutations, such as mutations located in the glycine-rich P loop of the N lobe and the activation segment and flanking regions within the kinase domain.
- the vemurafenib analog is dabrafenib.
- the AXL-ADC provided by the present disclosure is for use in treating an AXL-expressing melanoma resistant to a therapeutic agent with which the melanoma is being or has been treated, wherein the therapeutic agent is vemurafenib or a therapeutically effective analog or derivative thereof, and wherein the melanoma exhibits a mutation in BRAF.
- the melanoma exhibits a mutation in BRAF which renders the BRAF sensitive for inhibition by vemurafenib or the therapeutically effective analog or derivative.
- Non- limiting mutations include amino acid substitutions, deletions or insertions; preferably, the mutation is an amino acid substitution.
- mutations include, but are not limited to, V600 (e.g., V600E, V600K and V600D), residue L597 (e.g., L597R); and residue K601 (K601E).
- the mutation is selected from V600E, V600D, V600K, L597R and K601E.
- the at least one therapeutic agent consists of or comprises a chemotherapeutic agent selected from the group consisting of paclitaxel, docetaxel, cisplatin, doxorubicin, etoposide, carboplatin and metformin.
- the therapeutic agent is a microtubule-targeting agent, such as, e.g., paclitaxel, docetaxel or vincristine, or a therapeutically active analog or derivative of any thereof.
- the at least one therapeutic agent is a taxane, such as paclitaxel, docetaxel or a therapeutically active analog or derivative of paclitaxel or docetaxel.
- the chemotherapeutic agent is paclitaxel
- the cancer is cervical cancer, resistant to or having a high tendency for becoming resistant to paclitaxel.
- the chemotherapeutic agent is paclitaxel
- the cancer is an NSCLC, resistant to or having a high tendency for becoming resistant to paclitaxel.
- the chemotherapeutic agent is paclitaxel
- the cancer is an ovarian cancer, resistant to or having a high tendency for becoming resistant to paclitaxel.
- the chemotherapeutic is docetaxel and the cancer is a head and neck cancer, resistant to or having a high tendency for becoming resistant to docetaxel.
- the chemotherapeutic is docetaxel and the cancer is a gastric cancer, resistant to or having a high tendency for becoming resistant to docetaxel.
- the chemotherapeutic is docetaxel and the cancer is a breast cancer, resistant to or having a high tendency for becoming resistant to docetaxel.
- the chemotherapeutic is docetaxel and the cancer is a prostate cancer, resistant to or having a high tendency for becoming resistant to docetaxel.
- the chemotherapeutic is docetaxel and the cancer is a NSCLC, resistant to or having a high tendency for becoming resistant to docetaxel.
- the chemotherapeutic agent is cisplatin
- the cancer is an esophageal cancer, resistant to or having a high tendency for becoming resistant to cisplatin.
- the chemotherapeutic agent is cisplatin
- the cancer is an SCCHN, resistant to or having a high tendency for becoming resistant to cisplatin.
- the chemotherapeutic agent is carboplatin
- the cancer is an SCCHN, resistant to or having a high tendency for becoming resistant to carboplatin.
- the chemotherapeutic agent is cisplatin, and the cancer is an AML, resistant to or having a high tendency for becoming resistant to cisplatin.
- the chemotherapeutic agent is doxorubicin, and the cancer is an AML, resistant to or having a high tendency for becoming resistant to doxorubicin.
- the chemotherapeutic agent is etoposide
- the cancer is an AML, resistant to or having a high tendency for becoming resistant to etoposide.
- the chemotherapeutic agent is metformin
- the cancer is a prostate cancer, resistant to or having a high tendency for becoming resistant to metformin.
- the chemotherapeutic agent is cisplatin
- the cancer is an ovarian cancer, resistant to or having a high tendency for becoming resistant to cisplatin.
- the chemotherapeutic agent is doxorubicin
- the cancer is a non-small cell lung cancer (NSCLC), resistant to or having a high tendency for becoming resistant to doxorubicin.
- NSCLC non-small cell lung cancer
- the chemotherapeutic agent is temozolomide
- the tumor is an astrocytoma, resistant to or having a high tendency for becoming resistant to temozolomide.
- the chemotherapeutic agent is carboplatin
- the tumor is an astrocytoma, resistant to or having a high tendency for becoming resistant to carboplatin.
- the chemotherapeutic agent is vincristine
- the tumor is an astrocytoma, resistant to or having a high tendency for becoming resistant to vincristine.
- the invention relates to a method of treating a cancer in a subject in need thereof, wherein the cancer is, or has a high tendency for becoming, resistant to a therapeutic agent selected from a chemotherapeutic agent, a tyrosine kinase inhibitor, a PI3K inhibitor, a mAb/rTKI and a serine/threonine kinase inhibitor, comprising administering to the subject a therapeutically effective amount of an ADC comprising an antibody binding to human AXL.
- the therapeutic agent is selected from a chemotherapeutic agent, a tyrosine kinase inhibitor and a serine/threonine kinase inhibitor.
- the chemotherapeutic agent may be a taxane
- the tyrosine kinase inhibitor may be an EGF -inhibitor
- the serine/threonine kinase inhibitor may be a BRAF- or MEK-inhibitor.
- the cancer is an AXL-expressing cancer.
- the invention relates to a method of treating a NSCLC resistant to eriotinib in a subject, the method comprising administering to the subject an ADC comprising an antibody binding to human AXL.
- the method further comprises administering eriotinib, or an analog or derivative thereof, to the subject.
- the cancer is an AXL-expressing cancer.
- the invention relates to a method of treating a melanoma resistant to vemurafenib in a subject, wherein the melanoma exhibits a mutation in B AF and the mutation providing for vemurafenib inhibition of BRAF kinase activity of the mutant BRAF, the method comprising administering to the subject an ADC comprising an antibody binding to human AXL.
- the mutation is an amino acid substitution in residue V600, L597 and/or K601.
- the mutation is selected from V600E, V600D, V600K, L597R and K601E.
- the method further comprises administering vemurafenib, or an analog or derivative thereof, to the subject.
- the analog is dabrafenib.
- the cancer is an AXL-expressing cancer.
- the invention relates to a method of treating a cervical cancer resistant to paclitaxel in a subject, the method comprising administering to the subject an ADC comprising an antibody binding to human AXL. In one embodiment, the method further comprises administering paclitaxel, or an analog or derivative thereof, to the subject. In one embodiment, the cancer is an AXL-expressing cancer.
- a physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
- a pharmaceutical composition it is to be understood also to comprise a composition as such, or vice versa.
- the physician could start doses of the AXL-ADC employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
- a suitable dose will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen. Such an effective dose will generally depend upon the factors described above.
- an "effective amount" for therapeutic use may be measured by its ability to stabilize the progression of disease.
- the ability of a compound to inhibit cancer may, for example, be evaluated in an animal model system predictive of efficacy in human tumors.
- this property of a composition may be evaluated by examining the ability of the compound to inhibit cell growth or to induce cytotoxicity by in vitro assays known to the skilled practitioner.
- a therapeutically effective amount of a therapeutic compound may decrease tumor size, or otherwise ameliorate symptoms in a subject.
- One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected. For example, as already indicated, the National Comprehensive Cancer Network (NCCN, www.nccn.org) and European Society for Medical Oncology (ESMO, www.esmo.org/Guidelines) guidelines for assessing cancer treatments can be used.
- An exemplary, non-limiting range for a therapeutically effective amount of an AXL- ADC of the invention is 0.02-100 mg/kg, such as about 0.02-30 mg/kg, such as about 0.05-10 mg/kg, 0.1-5 mg/kg or 0.1-3 mg/kg, for example about 0.5-3 mg/kg or 0.5-2 mg/kg.
- Administration may e.g. be intravenous, intramuscular, intraperitoneal, or subcutaneous, and for instance administered proximal to the site of the target.
- Dosage regimens in the above methods of treatment and uses are adjusted to provide the optimum desired response [e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
- the efficacy-safety window is optimized by lowering specific toxicity such as for example by lowering the drug-antibody ratio (DA ) and/or mixing of AXL-ADC with unlabeled anti-AXL antibody.
- DA drug-antibody ratio
- the efficacy of the treatment is monitored during the therapy, e.g. at predefined points in time. Methods for measuring efficacy generally depend on the particular type of cancer and are well known to a person skilled in the art. In one embodiment, the efficacy may be monitored, by visualization of the disease area, or by other diagnostic methods described further herein, e.g. by performing one or more PET-CT scans, for example using a labeled anti-AXL antibody, fragment or mini-antibody derived from an AXL-specific antibody.
- an effective daily dose of a an AXL-ADC may be two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
- the AXL-ADCs are administered by slow continuous infusion over a long period, such as more than 24 hours, in order to minimize any unwanted side effects.
- An effective dose of an AXL-ADC may also be administered using a weekly, biweekly or triweekly dosing period.
- the dosing period may be restricted to, e.g., 8 weeks, 12 weeks or until clinical progression has been established.
- an AXL-ADC is administered either once every 3 weeks (1Q3W) or three administrations over 4 weeks (3Q4W) so that the patient receives sixteen or twelve cycles of AXL-ADC at three week or four-week intervals for, e.g., 48 weeks, extending or repeating the regimen as needed.
- the AXL-ADC may be administered by infusion in a weekly dosage of between 10 and 500 mg/m 2 , such as between 200 and 400 mg/m 2 .
- Such administration may be repeated, e.g., 1 to 8 times, such as 3 to 5 times.
- the administration may be performed by continuous infusion over a period of from 1 to 24 hours, such as from 1 to 12 hours.
- the AXL-ADC is administered by infusion every three weeks in a dosage of between 10 and 500 mg/m 2 , such as between 50-200 mg/m 2 .
- Such administration may be repeated, e.g., 1 to 8 times, such as 3 to 5 times.
- the administration may be performed by continuous infusion over a period of from 1 to 24 hours, such as from 1 to 12 hours.
- an AXL-ADC is administered as a single dose of about 0.1-10 mg/kg, such as about 1-3 mg/kg, every week or every third week for up to twelve times, up to eight times, or until clinical progression.
- the administration may be performed by continuous infusion over a period of from 1 to 24 hours, such as from 1 to 12 hours. Such regimens may be repeated one or more times as necessary, for example, after 6 months or 12 months.
- the dosage may be determined or adjusted by measuring the amount of compound of the present invention in the blood upon administration by for instance taking out a biological sample and using anti-idiotypic antibodies which target the antigen binding region of the anti-AXL antibodies.
- the AXL-ADCs are administered as maintenance therapy, such as, e.g., once a week for a period of six months or more.
- maintenance therapy means therapy for the purpose of avoiding or delaying the cancer's progression or return.
- maintenance therapy can be used to avoid to delay return of the cancer.
- maintenance therapy can be used to slow the growth of the cancer, e.g., to lengthen the life of the patient.
- treatment according to the present invention may be provided as a daily dosage of a compound of the present invention in an amount of about 0.1-100 mg/kg, such as about 0.1-50 mg/kg, such as about 0.2, 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg/kg, per day, on at least one of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively, at least one of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 after initiation of treatment, or any combination thereof, using single or divided doses every 24, 12, 8, 6, 4, or 2 hours, or any combination thereof.
- compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the dosage unit forms of the present invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
- the AXL-ADC can be used in combination with at least one additional therapeutic agent.
- the at least one additional therapeutic agent may comprise, or consist of, the chemotherapeutic agent, tyrosine kinase inhibitor, PI3K inhibitor, mAb/rTKI and/or serine/threonine kinase inhibitor to which the cancer or tumor is resistant or have a high tendency for developing resistance to, as set forth in the preceding embodiments.
- the AXL-ADC and the one or more therapeutic agents can be administered simultaneously, separately or sequentially.
- the combination is used for treating a cancer patient which has not received prior treatment with the at least one therapeutic agent.
- the combination is used for treating a cancer patient which has failed prior treatment with the at least one therapeutic agent. Efficient dosages and dosage regimens for the AXL-ADC and therapeutic agent(s) depend on the neoplasm, tumor or cancer to be treated and may be determined by the persons skilled in the art.
- the dosages and dosage regimens for the one or more therapeutic agents to be used in conjunction with the AXL-ADC are the same or essentially similar to those normally used in the treatment of such neoplasm, tumor or cancer with the one or more therapeutic agents.
- the dosages of the therapeutic agent(s) are lower than those normally used, but the dosage regimen is otherwise similar.
- the dosages of the therapeutic agent(s) are similar to those normally used, but the dosage regimen adjusted to fewer or less frequent administrations.
- the invention relates to a method of treating a cancer in a subject in need thereof, wherein the cancer is, or has a high tendency for becoming, resistant to a therapeutic agent selected from a chemotherapeutic agent, a tyrosine kinase inhibitor and a serine/threonine kinase inhibitor, comprising administering to the subject (i) an ADC comprising an antibody binding to human AXL and (ii) the therapeutic agent.
- the chemotherapeutic agent is a taxane
- the tyrosine kinase inhibitor is an EGF -inhibitor
- the serine/threonine kinase inhibitor a BRAF- or MEK-inhibitor.
- the cancer is an AXL-expressing cancer.
- the AXL-ADC may, e.g., be administered in a therapeutically effective amount according to a dosage regimen described in more detail above.
- the AXL-ADC may be administered in an amount of about 0.02-100 mg/kg, such as about 0.02-30 mg/kg, such as about 0.05-10 mg/kg either every 1 week (1Q1W), every 2 weeks (1Q2W) or every 3 weeks (1Q3W) or three administrations over 4 weeks (3Q4W) so that the patient receives sixteen or twelve cycles of AXL-ADC at three week or four-week intervals for, e.g., 48 weeks, extending, shortening or repeating the regimen as determined by the physician responsible.
- the invention relates to a method of treating a NSCLC resistant to eriotinib in a subject, the method comprising administering to the subject (i) an ADC comprising an antibody binding to human AXL and (ii) eriotinib, or a therapeutically effective analog or derivative thereof.
- the eriotinib may, for example, be administered orally at a dose of 50 to 300 mg, such as 100-200 mg, such as about 150 mg, once or twice daily, or every 2 or 3 days.
- the eriotinib is administered once daily at a dose of about 150 mg.
- the cancer is an AXL-expressing cancer.
- the invention relates to a method of treating a melanoma resistant to vemurafenib in a subject, wherein the melanoma exhibits a mutation in BRAF and the mutation providing for vemurafenib inhibition of BRAF kinase activity of the mutant BRAF, the method comprising administering to the subject (i) an ADC comprising an antibody binding to human AXL and (ii) vemurafenib, or a therapeutically effective analog or derivative thereof.
- the cancer is an AXL-expressing cancer.
- the mutation is an amino acid substitution in residue V600, L597 and/or K601.
- the mutation is selected from V600E, V600D, V600K, L597R and K601E.
- the vemurafenib may, for example, be administered orally at a dose of about 200-2000 mg, 500-1500 mg, such as about 1000 mg per day, e.g., 960 mg, administered as 4 x 240 mg tablets ql2hr (approximately 12 hr apart).
- the invention relates to a method of treating a melanoma resistant to dabrafenib in a subject, wherein the melanoma exhibits a mutation in BRAF and the mutation providing for dabrafenib inhibition of B AF kinase activity of the mutant BRAF, the method comprising administering to the subject (i) an ADC comprising an antibody binding to human AXL and (ii) dabrafenib, or a therapeutically effective analog or derivative thereof.
- the cancer is an AXL-expressing cancer.
- the mutation is an amino acid substitution in residue V600, L597 and/or K601.
- the mutation is selected from V600E, V600D, V600K, L597R and K601E.
- the dabrafenib may, for example, be administered orally to the subject at a dose of about 50-300 mg, such as about 100-200 mg, such as about 150 mg, once or twice daily or every 2 or 3 days.
- the dabrafenib is administered as 150 mg orally twice daily, e.g., at least lhr before a meal or at least 2 hrs after a meal.
- the invention relates to a method of treating a melanoma resistant to dabrafenib, trametinib or both in a subject, wherein the melanoma exhibits a mutation in BRAF and the mutation providing for dabrafenib inhibition of BRAF kinase activity of the mutant BRAF, the method comprising administering to the subject (i) an ADC comprising an antibody binding to human AXL, (ii) dabrafenib, or a therapeutically effective analog or derivative thereof and (iii) trametinib or a therapeutically effective analog or derivative thereof.
- the cancer is an AXL-expressing cancer.
- the mutation is an amino acid substitution in residue V600, L597 and/or K601. In one embodiment, the mutation is selected from V600E, V600D, V600K, L597R and K601E.
- the dabrafenib may, for example, be administered orally to the subject at a dose of about 50-300 mg, such as about 100-200 mg, such as about 150 mg, once or twice daily or every 2 or 3 days. Preferably, the dabrafenib is administered as 150 mg orally twice daily, e.g., at least lhr before a meal or at least 2 hrs after a meal.
- the tramatenib may, for example, be administered orally at a dose of about 0.5 to 5 mg, such as about 1 to 4 mg, such as about 2-3 mg, such as about 2 mg, once or twice daily or every 2, 3 or 4 days, such as once daily.
- the invention relates to a method of treating a cervical cancer resistant to a taxane in a subject, the method comprising administering to the subject (i) an ADC comprising an antibody binding to human AXL and (ii) a taxane to the subject.
- the cancer is an AXL-expressing cancer.
- the taxane is paclitaxel or a therapeutically effective analog or derivative thereof, such as docetaxel.
- the paclitaxel may be administered intravenously (iv) to the subject, for example at a dose of about 100-500 mg/m2, such as about 125-400 mg/m2, such as about 135 mg/m2, 175 mg/m2 or 250mg/m2 over a few hours (e.g., 3 hrs), and the treatment repeated every 1, 2, 3, 4, 5 weeks, such as every 3 weeks.
- the paclitaxel may be administered intravenously as albumin-bound paclitaxel (nab-paclitaxel), e.g., at a dose of about 50- 400 mg/m2, such as about 75-300 mg/m2, such as about 100-200 mg/m2, such as about 125 mg/m2 over a period over 30 min to 1 hr or more and the once per week, and repeating the treatment twice per week, or once every 2 or 3 weeks, e.g., once per week.
- albumin-bound paclitaxel e.g., at a dose of about 50- 400 mg/m2, such as about 75-300 mg/m2, such as about 100-200 mg/m2, such as about 125 mg/m2 over a period over 30 min to 1 hr or more and the once per week, and repeating the treatment twice per week, or once every 2 or 3 weeks, e.g., once per week.
- Docetaxel may, in turn, be administered iv at a dose of about 25-500 mg/m2, such as about 50-300 mg/m2, such as about 75-200 mg/m2, such as about 100 mg/m2 over 30 minutes to 2 hrs, such as 1 hr, and the treatment repeated every 1, 2, 3, 4 or 5 weeks, such as every 3 weeks.
- the AXL-ADC is used, alone or in combination with the therapeutic agent, to treat recurrent cancer in a subject, where the cancer recurred after an initial treatment with the therapeutic agent. Should the cancer recur yet again after the initial treatment with AXL-ADC, the AXL-ADC can be used again, alone or together with the therapeutic agent, to treat the recurrent cancer.
- the invention relates to a method of selecting a subject suffering from a cancer for treatment with a combination of an AXL-ADC and a therapeutic agent selected from a chemotherapeutic agent, a TKI, a PI3Ki, a mAb/rTKI and a S/Th Kl, comprising determining
- the therapeutic agent is a chemotherapeutic agent, a TKI or S/Th Kl.
- the invention relates to a method of treating a subject diagnosed with having a melanoma which is, or has a high tendency for becoming, resistant to vemurafenib or a therapeutically effective analog or derivative thereof, comprising administering a therapeutically effective amount of an ADC comprising an antibody binding to human AXL.
- the invention relates to a method of determining if a subject suffering from melanoma is suitable for treatment with a combination of (i) vemurafenib or a therapeutically effective analog or derivative thereof and (ii) an ADC comprising an antibody which binds to human AXL, wherein the subject is undergoing or has undergone treatment with vemurafenib (or the analog or derivative), and is determined or suspected to be resistant to the vemurafenib (or the analog or derivative), thus determining that the subject is suitable for the treatment.
- the melanoma expresses AXL.
- the analog is dabrafenib.
- the invention relates to a method of treating a subject diagnosed with a cervical cancer which is, or has a high tendency for becoming, resistant to paclitaxel or a therapeutically effective analog or derivative thereof, such another taxane (e.g., docetaxel), comprising administering a therapeutically effective amount of an ADC comprising an antibody binding to human AXL.
- a subject diagnosed with a cervical cancer which is, or has a high tendency for becoming, resistant to paclitaxel or a therapeutically effective analog or derivative thereof, such another taxane (e.g., docetaxel)
- administering a therapeutically effective amount of an ADC comprising an antibody binding to human AXL.
- the invention relates to a method of determining if a subject suffering from cervical cancer is suitable for treatment with a combination of (i) paclitaxel or a therapeutically effective analog or derivative thereof, such as another taxane (e.g., docetaxel) and (ii) an ADC comprising an antibody which binds to human AXL, wherein the subject is undergoing or has undergone treatment with paclitaxel and is determined or suspected to be resistant to the paclitaxel, thus determining that the subject is suitable for the treatment.
- it may be determined if the cervical cancer expresses AXL.
- the resistant neoplasm, tumor or cancer to be treated with an anti-AXL-ADC has been determined to express AXL.
- this is achieved by detecting levels of AXL antigen or levels of cells which express AXL on their cell surface in a sample taken from a patient.
- the patient may, for example, suffer from a cervical cancer, melanoma or NSCLC.
- the AXL antigen to be detected can be soluble AXL antigen, cell-associated AXL antigen, or both.
- the sample to be tested can, for example, be contacted with an anti-AXL antibody under conditions that allow for binding of the antibody to AXL, optionally along with a control sample and/or control antibody binding to an irrelevant antigen. Binding of the antibody to AXL can then be detected (e.g., using an ELISA).
- the level of anti-AXL antibody or anti-AXL antibody AXL complex is analyzed in both samples and a statistically significant higher level of anti- AXL antibody or anti-AXL antibody-AXL complex in the test sample shows a higher level of AXL in the test sample compared with the control sample, indicating a higher expression of AXL.
- conventional immunoassays useful for such purposes include, without limitation, ELISA, IA, FACS assays, plasmon resonance assays, chromatographic assays, tissue immunohistochemistry, Western blot, and/or immunoprecipitation.
- a tissue sample may be taken from a tissue known or suspected of containing AXL antigen and/or cells expressing AXL.
- in situ detection of AXL expression may be accomplished by removing a histological specimen such as a tumor biopsy or blood sample from a patient, and providing the anti-AXL antibody to such a specimen after suitable preparation of the specimen.
- the antibody may be provided by applying or by overlaying the antibody to the specimen, which is then detected using suitable means.
- the anti-AXL antibody can be labeled with a detectable substance to allow AXL-bound antibody to be detected.
- the level of AXL expressed on cells in a sample can also be determined according to the method described in Example 23, where AXL expression on the plasma membrane of human tumor cell lines was quantified by indirect immunofluorescence using QIFIKIT analysis (DAKO, Cat nr K0078), using a monoclonal anti-AXL antibody (here: mouse monoclonal antibody ab89224; Abeam, Cambridge, UK). Briefly, a single-cell suspension is prepared, and optionally washed. The next steps are performed on ice.
- the cells are seeded, e.g., at 100,000 cells per well or tube, and thereafter pelleted and resuspended in 50 ⁇ antibody sample at a concentration of 10 ⁇ g/mL, optionally adding a control antibody to a parallel sample. After an incubation of 30 minutes at 4 Q C, cells are pelleted and resuspended in 150 ⁇ FACS buffer, and the amount of AXL determined by FACS analysis using, e.g., a secondary, FITC-labelled antibody binding to the anti-AXL and control antibodies.
- the antibody binding capacity (ABC) an estimate for the number of AXL molecules expressed on the plasma membrane, was calculated using the mean fluorescence intensity of the AXL antibody-stained cells, based on the equation of a calibration curve as described in Example 23 (interpolation of unknowns from the standard curve).
- the level of AXL on AXL-expressing cells is estimated to at least 5000, such as at least 8000, such as at least 13000.
- the presence or level of AXL-expressing cells in a neoplasm, tumor or cancer is assessed by in vivo imaging of detectably labelled anti-AXL antibodies according to methods known in the art.
- a significantly higher signal from a site, such as the known or suspected site of a tumor, than background or other control indicates overexpression of AXL in the tumor or cancer.
- ADCs suitable for use in the context of the present invention can be prepared from any anti-AXL antibody.
- Preferred anti-AXL antibodies are characterized by one or more of the AXL- binding properties, variable or hypervariable sequences, or a combination of binding and sequence properties, set out in the aspects and embodiments below.
- the antibody binds to AXL but does not compete for AXL binding with the ligand Growth Arrest-Specific 6 (Gas6).
- the anti- AXL antibody comprises at least one binding region comprising a VH region and a VL region, wherein the VH region comprises the CD 1, CDR2 and CDR3 sequences of SEQ ID Nos.: 36, 37 and 38, and the VL region comprises the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40.
- the ADC comprises such an anti-AXL antibody linked to a cytotoxic agent which is an auristatin or a functional peptide analog or derivate thereof, such as, e.g., monomethyl auristatin E, preferably via a maleimidocaproyl-valine-citrulline-p-aminobenzyloxy- carbonyl (mc-vc-PAB) linker.
- a cytotoxic agent which is an auristatin or a functional peptide analog or derivate thereof, such as, e.g., monomethyl auristatin E, preferably via a maleimidocaproyl-valine-citrulline-p-aminobenzyloxy- carbonyl (mc-vc-PAB) linker.
- antibody as used herein is intended to refer to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of either thereof, which has the ability to specifically bind to an antigen under typical physiological and/or tumor-specific conditions with a half-life of significant periods of time, such as at least about 30 minutes, at least about 45 minutes, at least about one hour, at least about two hours, at least about four hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, about 48 hours or more, about 3, 4, 5, 6, 7 or more days, etc., or any other relevant functionally-defined period (such as a time sufficient to induce, promote, enhance, and/or modulate a physiological response associated with antibody binding to the antigen and/or time sufficient for the antibody to be internalized).
- significant periods of time such as at least about 30 minutes, at least about 45 minutes, at least about one hour, at least about two hours, at least about four hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, about 48 hours or
- the binding region (or binding domain which may be used herein, both having the same meaning) which interacts with an antigen, comprises variable regions of both the heavy and light chains of the immunoglobulin molecule.
- the constant regions of the antibodies (Abs) may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system such as Clq, the first component in the classical pathway of complement activation.
- the term antibody as used herein includes fragments of an antibody that retain the ability to specifically interact, such as bind, to the antigen. It has been shown that the antigen-binding function of an antibody may be performed by fragments of a full-length antibody.
- binding fragments encompassed within the term "antibody” include (i) a Fab' or Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains, or a monovalent antibody as described in WO 2007/059782; (ii) F(ab') 2 fragments, bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting essentially of the VH and CHI domains; (iv) an Fv fragment consisting essentially of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., 1989), which consists essentially of a VH domain and is also called domain antibody (Holt et al., 2003); (vi) camelid or nanobodies (Revets et al., 2005) and (vii) an isolated complementarity determining region (CDR).
- the two domains of the Fv fragment, VL and VH are coded for by separate genes, they may be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain antibodies or single chain Fv (scFv), see for instance Bird et al. (1988) and Huston et al. (1988).
- single chain antibodies are encompassed within the term antibody unless otherwise noted or clearly indicated by context.
- fragments are generally included within the meaning of antibody, they collectively and each independently are unique features of the present invention, exhibiting different biological properties and utility.
- antibody also includes polyclonal antibodies, monoclonal antibodies (mAbs), antibody-like polypeptides, such as chimeric antibodies and humanized antibodies, as well as 'antibody fragments' or 'fragments thereof retaining the ability to specifically bind to the antigen (antigen-binding fragments) provided by any known technique, such as enzymatic cleavage, peptide synthesis, and recombinant techniques, and retaining the ability to be conjugated to a toxin.
- mAbs monoclonal antibodies
- antibody-like polypeptides such as chimeric antibodies and humanized antibodies
- antigen-binding fragments provided by any known technique, such as enzymatic cleavage, peptide synthesis, and recombinant techniques, and retaining the ability to be conjugated to a toxin.
- An antibody as generated can possess any isotype.
- immunoglobulin heavy chain or "heavy chain of an immunoglobulin” as used herein is intended to refer to one of the heavy chains of an immunoglobulin.
- a heavy chain is typically comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH) which defines the isotype of the immunoglobulin.
- the heavy chain constant region typically is comprised of three domains, CHI, CH2, and CH3.
- immunoglobulin as used herein is intended to refer to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains and one pair of heavy (H) chains, all four potentially inter-connected by disulfide bonds.
- the structure of immunoglobulins has been well characterized (see for instance Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989). Within the structure of the immunoglobulin, the two heavy chains are inter-connected via disulfide bonds in the so-called "hinge region".
- each light chain is typically comprised of several regions; a light chain variable region (abbreviated herein as VL) and a light chain constant region.
- the light chain constant region typically is comprised of one domain, CL.
- the VH and VL regions may be further subdivided into regions of hypervariability (or hypervariable regions which may be hypervariable in sequence and/or form of structurally defined loops), also termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (F s).
- Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy- terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
- CDR sequences are defined according to IMGT (see Lefranc et al. (1999) and Brochet et al. (2008)).
- antigen-binding region refers to a region of an antibody which is capable of binding to the antigen.
- the antigen can be any molecule, such as a polypeptide, e.g. present on a cell, bacterium, or virion.
- the terms "antigen” and “target” may, unless contradicted by the context, be used interchangeably in the context of the present invention.
- binding refers to the binding of an antibody to a predetermined antigen or target, typically with a binding affinity corresponding to a K D of about 10 "6 M or less, e.g. 10 "7 M or less, such as about 10 s M or less, such as about 10 "9 M or less, about 10 10 M or less, or about 10 11 M or even less when determined by for instance surface plasmon resonance (SPR) technology in a BIAcore 3000 instrument using the antigen as the ligand and the protein as the analyte, and binds to the predetermined antigen with an affinity corresponding to a K D that is at least ten-fold lower, such as at least 100 fold lower, for instance at least 1,000 fold lower, such as at least 10,000 fold lower, for instance at least 100,000 fold lower than its affinity for binding to a nonspecific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen.
- a nonspecific antigen e.g., BSA, casein
- K D (M)
- M the dissociation equilibrium constant of a particular antibody-antigen interaction
- k d (sec 1 ), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. Said value is also referred to as the k off value or off-rate.
- k a (M 1 x sec "1 ), as used herein, refers to the association rate constant of a particular antibody-antigen interaction. Said value is also referred to as the k on value or on-rate.
- K A (M 1 ), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction and is obtained by dividing k a by k d .
- AXL refers to the protein entitled AXL, which is also referred to as UFO or JTK11, a 894 amino acid protein with a molecular weight of 104-140 kDa that is part of the subfamily of mammalian TAM Receptor Tyrosine Kinases (RTKs). The molecular weight is variable due to potential differences in glycosylation of the protein.
- the AXL protein consists of two extracellular immunoglobulin-like (Ig-like) domains on the N-terminal end of the protein, two membrane-proximal extracellular fibronectin type III (FNIII) domains, a transmembrane domain and an intracellular kinase domain.
- AXL is activated upon binding of its ligand Gas6, by ligand- independent homophilic interactions between AXL extracellular domains, by autophosphorylation in presence of reactive oxygen species (Korshunov et al., 2012) or by transactivation through EGF (Meyer et al., 2013), and is aberrantly expressed in several tumor types.
- the AXL protein is encoded by a nucleic acid sequence encoding the amino acid sequence shown in SEQ ID NO:130 (human AXL protein: Swissprot P30530; cynomolgus AXL protein: Genbank accession HB387229.1)).
- ligand-independent homophilic interactions refers to association between two AXL molecules (expressed on neighboring cells) that occurs in absence of the ligand.
- antibody binding AXL refers to any antibody binding an epitope on the extracellular part of AXL.
- epitope means a protein determinant capable of specific binding to an antibody.
- Epitopes usually consist of surface groupings of molecules such as amino acids, sugar side chains or a combination thereof and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
- the epitope may comprise amino acid residues which are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding, such as amino acid residues which are effectively blocked or covered by the specific antigen binding peptide (in other words, the amino acid residue is within the footprint of the specific antigen binding peptide).
- ligand refers to a substance, such as a hormone, peptide, ion, drug or protein, that binds specifically and reversibly to another protein, such as a receptor, to form a larger complex.
- Ligand binding to a receptor may alter its chemical conformation, and determines its functional state. For instance, a ligand may function as agonist or antagonist.
- Gas6 refers to a 721 amino acid protein, with a molecular weight of 75-80 kDa, that functions as a ligand for the TAM family of receptors, including AXL.
- Gas6 is composed of an N-terminal region containing multiple gamma- carboxyglutamic acid residues (Gla), which are responsible for the specific interaction with the negatively charged phospholipid membrane.
- Ga gamma- carboxyglutamic acid residues
- Gas6 may also be termed as the "ligand to AXL”.
- monoclonal antibody refers to a preparation of antibody molecules of single molecular composition.
- a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
- human monoclonal antibody refers to antibodies displaying a single binding specificity which have variable and constant regions derived from human germline immunoglobulin sequences.
- the human monoclonal antibodies may be produced by a hybridoma which includes a B cell obtained from a transgenic or transchromosomal non-human animal, such as a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene, fused to an immortalized cell.
- a hybridoma which includes a B cell obtained from a transgenic or transchromosomal non-human animal, such as a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene, fused to an immortalized cell.
- ADC refers to an antibody drug conjugate, which in the context of the present invention refers to an anti-AXL antibody which is coupled to a therapeutic moiety, e.g., a cytotoxic moiety as described in the present application. It may e.g. be coupled with a linker to e.g. cysteine or with other conjugation methods to other amino acids.
- the moiety may e.g. be a drug or a toxin or the like.
- a “therapeutic moiety” means a compound which exerts a therapeutic or preventive effect when administered to a subject, particularly when delivered as an ADC as described herein.
- a "cytotoxic” or “cytostatic” moiety is a compound that is detrimental to [e.g., kills) cells.
- Some cytotoxic or cytostatic moieties for use in ADCs are hydrophobic, meaning that they have no or only a limited solubility in water, e.g., 1 g/L or less (very slightly soluble), such as 0.8 g/L or less, such as 0.6 g/L or less, such as 0.4 g/L or less, such as 0.3 g/L or less, such as 0.2 g/L or less, such as 0.1 g/L or less (practically insoluble).
- hydrophobic cytotoxic or cytostatic moieties include, but are not limited to, certain microtubulin inhibitors such as auristatin and its derivatives, e.g., MMAF and MMAE, as well as maytansine and its derivatives, e.g., DM1.
- the antibody has a binding affinity (K D ) in the range of 0.3xl0 "9 to 63xl0 "9 M to AXL, and wherein said binding affinity is measured using a Bio-layer Interferometry using soluble AXL extracellular domain.
- the binding affinity may be determined as described in Example 2.
- the antibody has a binding affinity of 0.3xl0 "9 to 63xl0 "9 M to the antigen, wherein the binding affinity is determined by a method comprising the steps of;
- soluble recombinant AXL extracellular domain refers to an AXL extracellular domain, corresponding to amino acids 1-447 of the full-length protein (SEQ ID NO:130; see Example 1) that has been expressed recombinantly. Due to absence of the transmembrane and intracellular domain, recombinant AXL extracellular domain is not attached to a, e.g. cell surface and stays in solution. It is well-known how to express a protein recombinantly, see e.g. Sambrook (1989), and thus, it is within the knowledge of the skilled person to provide such recombinant AXL extracellular domain.
- the antibody has a dissociation rate of 6.9x10 s s "1 to 9.7xl0 "3 s " ho AXL, and wherein the dissociation rate is measured by Bio-layer Interferometry using soluble recombinant AXL extracellular domain.
- the binding affinity may be determined as described above (and in Example 2).
- the antibody has a dissociation rate of 6.9x10 s s "1 to 9.7xl0 "3 s _1 to AXL, and wherein the dissociation rate is measured by a method comprising the steps of
- dissociation rate refers to the rate at which an antigen-specific antibody bound to its antigen, dissociates from that antigen, and is expressed as s 1 .
- dissociation rate refers to the antibody binding AXL dissociates from the recombinant extracellular domain of AXL, and is expressed as s 1 .
- the ADCs for the use of the present invention comprises an antibody- portion which binds to an extracellular domain of AXL without competing or interfering with Gas6 binding to AXL.
- the antibody binds to the extracellular domain Igldomain without competing or interfering with Gas6 binding to AXL.
- the antibody binds to the extracellular domain Igl and show no more than a 20% reduction in maximal Gas6 binding to AXL.
- the antibody show no more than a 15% reduction in maximal Gas6 binding to AXL.
- the antibody show no more than a 10% reduction in maximal Gas6 binding to AXL.
- the antibody show no more than a 5% reduction in maximal Gas6 binding to AXL.
- the antibody show no more than a 4% reduction in maximal Gas6 binding to AXL In one embodiment, the antibody show no more than a 2% reduction in maximal Gas6 binding to AXL. In one embodiment, the antibody show no more than a 1% reduction in maximal Gas6 binding. In one embodiment the antibody binds to the Ig2 domain in the AXL extracellular domain without competing or interfering with Gas6 binding to AXL.
- the antibody binds to the Ig2 domain in the AXL extracellular domain and show no more than a 20%, such as no more than 15%, such as no more than 10%, such as no more than 5%, such as no more than 4%, such as no more than 2%, such as no more than 1%, reduction in maximal Gas6 binding to AXL.
- the embodiment's ability to compete with or reduce Gas6 binding may be determined as disclosed in Example 2 or Example 12.
- the antibody binds to the Ig2 domain in the AXL extracellular domain without competing or interfering with maximal Gas6 binding to AXL.
- maximal antibody binding in the presence of Gas6 is at least 90%, such as at least 95%, such as at least 97%, such as at least 99%, such as 100%, of binding in absence of Gas6 as determined by a competition assay, wherein competition between said antibody binding to human AXL and said Gas6 is determined on A431 cells preincubated with Gas6 and without Gas6.
- the antibody does not compete for AXL binding with the ligand Gas6, wherein the competing for binding is determined in an assay comprising the steps of
- the antibody does not compete for binding with the ligand Gas6, wherein the competing for binding is determined in an assay comprising the steps of
- the antibody modulates AXL-associated signaling in an AXL- expressing cell of the when the cell is contacted with the antibody.
- the antibody does not modulate AXL-associated signaling in an AXL-expressing cell of the when the cell is contacted with the antibody.
- modulation of AXL-associated signalling includes modulation of intracellular signaling pathways such as the PI3K/AKT, mitogen-activated protein kinase (MAPK), STAT or NF-KB cascades.
- the anti-AXL antibody or AXL-ADC competes for binding to AXL with an antibody comprising a variable heavy (VH) region and a variable light (VL) region selected from the group consisting of:
- the term “competes with” or “cross-competes with” indicates that the antibody competes with the ligand or another antibody, e.g., a "reference” antibody in binding to an antigen, respectively.
- Example 2 describes an example of how to test competition of an anti-AXL antibody with the AXL-ligand Gas6.
- Preferred reference antibodies for cross-competition between two antibodies are those comprising a binding region comprising the VH region and VL region of an antibody herein designated 107, 148, 733, 154, 171, 183, 613, 726, 140, 154-M103L, 172, 181, 183- N52Q, 187, 608-01, 610-01, 613-08, 620-06 or 726-M101L, as set forth in Table 4.
- a particularly preferred reference antibody is the antibody designated 107.
- the anti-AXL antibody binds to the same epitope on AXL as any one or more of the antibodies according to the aforementioned embodiment, as defined by their VH and VL sequences, e.g., a VH region comprising SEQ ID No:l and a VL region comprising SEQ ID No:2
- Methods of determining an epitope to which an antibody binds are well-known in the art. Thus, the skilled person would know how to determine such an epitope. However, one example of determining whether an antibody binds within any epitope herein described may be by introducing point mutations into the extracellular domain of AXL extracellular domain, e.g., for the purpose of identifying amino acids involved in the antibody-binding to the antigen. It is within the knowledge of the skilled person to introduce point mutation(s) in the AXL extracellular domain and test for antibody binding to point mutated AXL extracellular domains, since the effect of point mutations on the overall 3D structure is expected to be minimal.
- Example 3 An alternative method was used in Example 3, wherein the AXL domain specificity was mapped by preparing a panel of human-mouse chimeric AXL mutants where the human Igl , Ig2, FN1 or FN2 domain had been replaced by its murine analog, and determining which mutant an anti-AXL antibody bound to.
- This method was based on the principle that these human AXL-specific antibodies recognized human but not mouse AXL. So, in separate and specific embodiments, the antibody binds to the Igl domain of AXL, the Ig2 domain of AXL, the FN1 domain of AXL, or the FN2 domain of AXL.
- a more high-resolution epitope-mapping method identifying AXL extracellular domain amino acids involved in antibody binding, was also used in this Example. Specifically, this method analyzed binding of the anti-AXL antibody to a library of AXL sequence variants generated by recombination of AXL sequences derived from species with variable levels of homology with the human AXL sequence (SEQ ID NO:130) in the extracellular domain. This method was based on the principle that these human AXL-specific antibodies recognize human AXL, but not the AXL from any of the other species used in the example.
- the antibody binds to an epitope within the Igl domain of AXL, and the antibody binding is dependent on one or more or all of the amino acids corresponding to positions L121 to Q129 or one or more or all of T112 to Q124 of human AXL, wherein the numbering of amino acid residues refers to their respective positions in human AXL (SEQ ID NO:130).
- the antibody binds to an epitope within the Igl domain of AXL, and antibody binding is dependent on the amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL.
- antibody binding is dependent on one or more or all amino acids in position L121, G122, H123, Q124, T125, F126, V127, S128 and Q129, corresponding to the amino acids involved in the binding of the antibody herein designated 107.
- antibody binding is dependent on one or more or all amino acid in position T112, G113, Q114, Y115, Q116, C117, L118,V119, F120, L121, G122, H123 and Q124.
- the antibody binds to an epitope within the Ig2 domain of AXL, and antibody binding is dependent on one or more or all of the amino acids corresponding to position D170 or the combination of D179 or one or more or all of the amino acids in positions T182 to 190 of human AXL. In one embodiment antibody binding is dependent on the amino acids in position T182, A183, P183, G184, H185, G186, P187, Q189 and R190.
- the antibody binds to an the FN1 domain of human AXL, and antibody binding is dependent on one or more or all of the amino acids corresponding to positions Q272 to A287 and G297 to P301 of human AXL. In one embodiment, antibody binding is dependent on the amino acids corresponding to positions Q272 to A287 and G297 to P301 of human AXL.
- the antibody binds to the FN2 domain of human AXL and antibody binding is dependent on one or more or all of the amino acids corresponding to positions A359, R386, and Q436 to K439 of human AXL.
- the antibody binds to an epitope within the Igl domain of AXL, and the epitope comprises or requires one or more or all of the amino acids corresponding to positions L121 to Q129 or one or more or all of T112 to Q124 of human AXL, wherein the numbering of amino acid residues refers to their respective positions in human AXL (SEQ ID NO:130).
- the antibody binds to an epitope within the Igl domain of AXL, and the epitope comprises or requires the amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL.
- the epitope comprises one or more or all amino acid in position L121, G122, H123, Q124, T125, F126, V127, S128 and Q129, corresponding to the amino acids involved in the binding of the antibody herein designated 107.
- the epitope comprises one or more or all amino acid in position T112, G113, Q114, Y115, Q116, C117, L118,V119, F120, L121, G122, H123 and Q124.
- the antibody binds to an epitope within the Ig2 domain of AXL, and the epitope comprises or requires one or more or all of the amino acids corresponding to position D170 or the combination of D179 or one or more or all of the amino acids in positions T182 to R190 of human AXL.
- the epitope comprises or requires the amino acids in position T182, A183, P183, G184, H185, G186, P187, Q189 and R190.
- the antibody binds to an epitope within the FN1 domain of human AXL, which epitope comprises or requires one or more or all of the amino acids corresponding to positions Q272 to A287 and G297 to P301 of human AXL.
- the epitope comprises or requires the amino acids corresponding to positions Q272 to A287 and G297 to P301 of human AXL.
- the antibody binds to an epitope within the FN2 domain of human AXL, which epitope comprises or requires one or more or all of the amino acids corresponding to positions A359, R386, and Q436 to K439 of human AXL.
- the antibody binds to an epitope within the FNl-like domain of human AXL.
- the antibody binds to an epitope on AXL which epitope is recognized by any one of the antibodies defined by
- VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 53, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 53, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 53, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 54, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 55, GAS, and 56, respectively [154-M103L];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 57,
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 60, GAS, and 61, respectively, [171];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 62, 63, and 64, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 65, GAS, and 66, respectively, [172];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 67, 68, and 69, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 70, GAS, and 71, respectively, [181];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 73, and 75, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 73, and 75, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 73, and 75, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 74, and 75, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 76, ATS, and 77, respectively, [183-N52Q];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 78,
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 81, AAS, and 82, respectively, [187];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 83, 84, and 85, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 86, GAS, and 87, respectively, [608-01];
- n a VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 88, 89, and 90, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 91, GAS, and 92, respectively, [610-01]; n) a VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 93, 94, and 95, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 96, GAS, and 97, respectively, [613];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 98, 99, and 100, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 10, DAS, and 102, respectively, [613-08];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 103, 104, and 105, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 106, GAS, and 107, respectively, [620-06];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 108,
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 112, AAS, and 113, respectively, [726];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 111, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 112, AAS, and 113, respectively, [726-M101L];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 41, 42, and 43, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 44, AAS, and 45, respectively, [140];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ I D Nos.: 93, 94, and 95, respectively, and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 128, XAS, wherein X is D or G, and 129, respectively, [613 / 613-08];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 119, and 120, respectively; and a VL region comprising CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 49, AAS, and 50, respectively, [148/140];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 123,
- VL region comprising CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 60, GAS, and 61, respectively [171 / 172 / 181];
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 121, 109, and 122, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 112, AAS, and 113, respectively [726 / 187]; and
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ I D Nos.:93, 126, and 127, respectively; and a VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ I D Nos.: 96, GAS, and 97, respectively [613 / 608-01 / 610-01 / 620-06].
- the antibody binds to an epitope on AXL which epitope is recognized by any one of the antibodies defined by comprising a binding regon comprising the VH and VL sequences of an antibody selected from those herein designated 107, 061, 137, 148, 154- M103L, 171, 183-N52Q, 511, 613, 726-M102L and 733.
- these anti-AXL antibodies internalize, and are thus suitable for an ADC approach.
- the antibody comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of:
- VH region comprising the CD 1, CDR2, and CDR3 sequences of SEQ ID Nos.:36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:39, GAS, and 40, respectively, [107];
- VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:55, GAS, and 56, respectively [154-M103L];
- VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:57, 58, and 59, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:60, GAS, and 61, respectively, [171];
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.:112, AAS, and 113, respectively, [726];
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.:112, AAS, and 113, respectively, [726-M101L];
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ
- (x) a VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.:93, 126, and
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ I D Nos.:96, GAS, and 97, respectively [613 / 608-01 / 610-01 / 620-06].
- the antibody comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of:
- the present invention also provides antibodies comprising functional variants of the VL region, VH region, or one or more CDRs of the antibodies mentioned above.
- a functional variant of a VL, VH, or CDR used in the context of an AXL antibody still allows the antibody to retain at least a substantial proportion (at least about 50%, 60%, 70%, 80%, 90%, 95%, 99% or more) of the affinity/avidity and/or the specificity/selectivity of the parent antibody and in some cases such an AXL antibody may be associated with greater affinity, selectivity and/or specificity than the parent antibody.
- Such functional variants typically retain significant sequence identity to the parent antibody.
- the comparison of sequences and determination of percent identity between two sequences may be accomplished using a mathematical algorithm, which is well-known in the art.
- sequence identity between two amino acid sequences may, for example, be determined using the Needleman-Wunsch algorithm (Needleman and Wunsch, 1970, J. Mol. Biol. 48: 443-453) as implemented in the Needle program of the EMBOSS package (EMBOSS: The European Molecular Biology Open Software Suite, Rice et al., 2000, Trends Genet. 16: 276-277), preferably version 5.0.0 or later.
- the parameters used are gap open penalty of 10, gap extension penalty of 0.5, and the EBLOSUM62 (EM BOSS version of BLOSUM62) substitution matrix.
- the output of Needle labeled "longest identity" (obtained using the -nobrief option) is used as the percent identity and is calculated as follows:
- the VH, VL and/or CDR sequences of variants may differ from those of the parent antibody sequences through mostly conservative substitutions; for instance at least about 35%, about 50% or more, about 60% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, ⁇ e.g., about 65-95%, such as about 92%, 93% or 94%) of the substitutions in the variant are conservative amino acid residue replacements.
- the VH, VL and/or CD sequences of variants may differ from those of the parent antibody sequences through mostly conservative substitutions; for instance 10 or less, such as 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, 2 or less or 1 of the substitutions in the variant are conservative amino acid residue replacements.
- Embodiments are also provided wherein mutations or substitutions of up to five mutations or substitutions are allowed across the three CDR sequences in the variable heavy chain and/or variable light chain of the preceding embodiment.
- the up to five mutations or substitutions may be distributed across the three CDR sequences of the variable heavy chain and the three CDR sequences of the variable light chain.
- the up to five mutations or substitutions may be distributed across the six CDR sequences of the binding region.
- the mutations or substitutions may be of conservative, physical or functional amino acids such that mutations or substitutions do not change the epitope or preferably do not modify binding affinity to the epitope more than 30 %, such as more than 20 % or such as more than 10%.
- the conservative, physical or functional amino acids are selected from the 20 natural amino acids found i.e, Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gin, Cys, Gly, Pro, Ala, lie, Leu, Met, Phe, Trp, Tyr and Val.
- the antibody comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of VH and VL sequences at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to:
- the present invention also provides antibodies comprising functional variants of the VL region, VH region, or one or more CDRs of the antibodies of the examples.
- a functional variant of a VL, VH, or CDR used in the context of an AXL antibody still allows the antibody to retain at least a substantial proportion (at least about 50%, 60%, 70%, 80%, 90%, 95%, 99% or more) of the affinity/avidity and/or the specificity/selectivity of the parent antibody and in some cases such an AXL antibody may be associated with greater affinity, selectivity and/or specificity than the parent antibody.
- Such functional variants typically retain significant sequence identity to the parent antibody.
- the comparison of sequences and determination of percent identity between two sequences may be accomplished using a mathematical algorithm, which is well-known in the art.
- the VH, VL and/or CDR sequences of variants may differ from those of the parent antibody sequences through mostly conservative substitutions; for instance at least about 35%, about 50% or more, about 60% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, ⁇ e.g., about 65-95%, such as about 92%, 93% or 94%) of the substitutions in the variant are conservative amino acid residue replacements.
- the VH, VL and/or CD sequences of variants may differ from those of the parent antibody sequences through mostly conservative substitutions; for instance 10 or less, such as 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, 2 or less or 1 of the substitutions in the variant are conservative amino acid residue replacements.
- Embodiments are also provided wherein mutations or substitutions of up to five mutations or substitutions are allowed across the three CDR sequences in the variable heavy chain and/or variable light chain of the preceding embodiment.
- the up to five mutations or substitutions may be distributed across the three CDR sequences of the variable heavy chain and the three CDR sequences of the variable light chain.
- the up to five mutations or substitutions may be distributed across the six CDR sequences of the binding region.
- the mutations or substitutions may be of conservative, physical or functional amino acids such that mutations or substitutions do not change the epitope or preferably do not modify binding affinity to the epitope more than 30 %, such as more than 20 % or such as more than 10%.
- the conservative, physical or functional amino acids are selected from the 20 natural amino acids found i.e, Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gin, Cys, Gly, Pro, Ala, lie, Leu, Met, Phe, Trp, Tyr and Val.
- the antibody comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of VH and VL sequences at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to:
- the antibody comprises at least one binding region comprising the VH and VL CDR1, CDR2, and CDR3 sequences of an anti-AXL antibody known in the art, e.g., an antibody described in any of Leconet et al. (2013), Li et al. (2009), Ye et al. (2010), lida et al.
- the antibody is murine antibody 1613F12 or a chimeric or a humanized variant thereof as described in WO2014174111 (Pierre Fabre Medicament), wherein the VH and VL sequences of the mouse antibody 1613F12 are presented as SEQ ID:8 and SEQ ID:7, respectively.
- the VH sequence of the humanized antibody variant of 1613F12 is selected from the sequences disclosed therein as SEQ ID NO:29 to 49 and SEQ ID NO:82
- the VL sequence of the humanized antibody variant of 1613F12 is selected from the sequences disclosed therein as SEQ ID NO:17 to 28 and SEQ ID: 81.
- One specific antibody comprises the VH and VL sequences disclosed therein as SEQ ID NO:29 and 17, respectively.
- the VH CDR1, CDR2 and CDR3 sequences of mouse, chimeric and humanized 1613F12 are SEQ ID NO:4, 5 and 6, respectively and the VL CDR1, CDR2 and CDR3 sequences of mouse and humanized 1613F12 are disclosed therein as SEQ ID NO:l, 2, and 3, respectively.
- the antibody is an antibody described in WO2011159980 (Hoffman-La Roche), which is hereby incorporated by reference in its entirety, particularly paragraphs [0127] through [0229] (pages 28-52).
- the antibody may comprise the VH and VL hypervariable regions (HVR), or the VH and VL regions, of antibody YW327.6S2, which are disclosed therein as SEQ ID NOS:7, 8 and 9 (VH HVR1, 2 and 3, respectively), SEQ ID NOS:10, 11 and 12 (VL HVR1, 2 and 3, respectively) and SEQ ID NOS:103 and 104 (VH and VL sequences, respectively).
- the antibody mediates antibody-mediated crosslinking or clustering (e.g., due to the Fc-region of AXL-bound antibodies binding to FcR-expressing cells) of AXL molecules on the surface of a cell, which can lead to apoptosis of the cell.
- the antibody induces an Fc-dependent cellular response such as
- the antibody-portion of the antibody is typically full-length and of an isotype leading to an ADCC or ADCP response, such as, e.g., an lgGl,K isotype.
- the antibody induces a CDC response against an AXL-expressing cell after binding of the AXL-specific antibody to the plasma membrane of the AXL-expressing cell in the presence of complement proteins, such as complement proteins present in normal human serum, that may be activated.
- complement proteins such as complement proteins present in normal human serum
- the antibody is typically full-length and of an isotype capable of inducing activation of the complement system, such as, e.g., an lgGl, K isotype.
- the antibody and/or ADC may further be characterized by internalization upon binding to AXL. Accordingly, in one embodiment, the antibody and/or ADC is internalized and trafficked to lysosomes for specific (i.e. cleavable linker) or non-specific (non-cleavable linker) proteolytic cleavage of the anti-AXL antibody-linker-drug complex.
- the antibody interferes with AXL-mediated regulation of the innate or adaptive immune response, such as by binding of the antibody to AXL-expressing macrophages, dendritic cells or NK cells.
- the therapeutic moiety of the ADC is linked to the antibody moiety via a linker allowing for release of the drug once the ADC is internalized, e.g., by a change in pH or reducing conditions.
- a linker Suitable linker technology is known in the art, as described herein.
- the antibody comprises a heavy chain of an isotype selected from the group consisting of IgGl, lgG2, lgG3, and lgG4. In a further embodiment, the antibody comprises a heavy chain of an isotype selected from the group consisting of a human IgGl, lgG2, lgG3, and lgG4.
- isotype refers to the immunoglobulin class (for instance
- each heavy chain isotype can be combined with either a kappa ( ⁇ ) or lambda ( ⁇ ) light chain.
- the isotype is IgGl, such as human IgGl, optionally allotype
- the antibody is a full-length monoclonal antibody, optionally a full-length human monoclonal lgGl, K antibody.
- full-length antibody when used herein, refers to an antibody (e.g., a parent or variant antibody) which contains all heavy and light chain constant and variable domains corresponding to those that are normally found in a wild-type antibody of that isotype.
- a full-length antibody according to the present invention may be produced by a method comprising the steps of (i) cloning the CD sequences into a suitable vector comprising complete heavy chain sequences and complete light chain sequence, and (ii) expressing the complete heavy and light chain sequences in suitable expression systems. It is within the knowledge of the skilled person to produce a full-length antibody when starting out from either CDR sequences or full variable region sequences. Thus, the skilled person would know how to generate a full-length antibody according to the present invention.
- the antibody is a human antibody.
- human antibody is intended to include antibodies having variable and framework regions derived from human germline immunoglobulin sequences and a human immunoglobulin constant domain.
- the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations, insertions or deletions introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
- human antibody as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another non-human species, such as a mouse, have been grafted onto human framework sequences.
- a human antibody is "derived from" a particular germline sequence if the antibody is obtained from a system using human immunoglobulin sequences, for instance by immunizing a transgenic mouse carrying human immunoglobulin genes or by screening a human immunoglobulin gene library, and wherein the selected human antibody is at least 90%, such as at least 95%, for instance at least 96%, such as at least 97%, for instance at least 98%, or such as at least 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene.
- a human antibody derived from a particular human germline sequence will display no more than 20 amino acid differences, e.g. no more than 10 amino acid differences, such as no more than 9, 8, 7, 6 or 5, for instance no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene.
- the antibody according to the present invention may comprise amino acid modifications in the immunoglobulin heavy and/or light chains.
- amino acids in the Fc region of the antibody may be modified.
- Fc region refers to a region comprising, in the direction from the N- to C-terminal end of the antibody, at least a hinge region, a CH2 region and a CH3 region.
- An Fc region of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system.
- hinge region refers to the hinge region of an immunoglobulin heavy chain.
- the hinge region of a human IgGl antibody corresponds to amino acids 216-230 according to the Eu numbering as set forth in Kabat et al. (1991).
- the hinge region may also be any of the other subtypes as described herein.
- CHI region refers to the CHI region of an immunoglobulin heavy chain.
- the CHI region of a human IgGl antibody corresponds to amino acids 118-215 according to the Eu numbering as set forth in Kabat et al. (1991) .
- the CHI region may also be any of the other subtypes as described herein.
- CH2 region refers to the CH2 region of an immunoglobulin heavy chain.
- the CH2 region of a human IgGl antibody corresponds to amino acids 231-340 according to the Eu numbering as set forth in Kabat et al. (1991) .
- the CH2 region may also be any of the other subtypes as described herein.
- CH3 region refers to the CH3 region of an immunoglobulin heavy chain.
- the CH3 region of a human IgGl antibody corresponds to amino acids 341-447 according to the Eu numbering as set forth in Kabat et al. (1991).
- the CH3 region may also be any of the other subtypes as described herein.
- the antibody is an effector-function-deficient antibody, a stabilized lgG4 antibody or a monovalent antibody.
- the heavy chain has been modified such that the entire hinge region has been deleted.
- sequence of the antibody has been modified so that it does not comprise any acceptor sites for N-linked glycosylation.
- the antibody is a single-chain antibody.
- the present invention relates to a multispecific antibody comprising at least a first binding region of an antibody according to any aspect or embodiment herein described, and a second binding region which binds a different target or epitope than the first binding region.
- multispecific antibody refers to antibodies wherein the binding regions bind to at least two, such as at least three, different antigens or at least two, such as at least three, different epitopes on the same antigen.
- the present invention relates to the use of an ADC comprising a bispecific antibody comprising a first binding region of an antibody according to any aspect or embodiments herein described, and a second binding region which binds a different target or epitope than the first binding region.
- binding molecules such as antibodies wherein the binding regions of the binding molecule bind to two different antigens or two different epitopes on the same antigen.
- bispecific antibody refers to an antibody having specificities for at least two different, typically non-overlapping, epitopes. Such epitopes may be on the same or different targets. If the epitopes are on different targets, such targets may be on the same cell or different cells, cell types or structures, such as extracellular tissue.
- different target refers to another protein, molecule or the like than AXL or an AXL fragment.
- the bispecific antibody of the present invention is a diabody, a cross-body, such as CrossMabs, or a bispecific antibody obtained via a controlled Fab arm exchange (such as described in WO 2011/131746, Genmab A/S).
- bispecific antibodies include but are not limited to (i) IgG-like molecules with complementary CH3 domains to force heterodimerization; (ii) recombinant IgG-like dual targeting molecules, wherein the two sides of the molecule each contain the Fab fragment or part of the Fab fragment of at least two different antibodies; (iii) IgG fusion molecules, wherein full length IgG antibodies are fused to extra Fab fragment or parts of Fab fragment; (iv) Fc fusion molecules, wherein single chain Fv molecules or stabilized diabodies are fused to heavy-chain constant-domains, Fc-regions or parts thereof; (v) Fab fusion molecules, wherein different Fab- fragments are fused together, fused to heavy-chain constant-domains, Fc-regions or parts thereof; and (vi) ScFv-and diabody-based and heavy chain antibodies (e.g., domain antibodies, Nanobodies ® ) wherein different single chain Fv molecules or different diabodies or different heavy chain antibodies (e
- IgG-like molecules with complementary CH3 domains molecules include but are not limited to the Triomab ® (Trion Pharma/Fresenius Biotech, WO/2002/020039), Knobs- into-Holes (Genentech, WO9850431), CrossMAbs (Roche, WO 2009/080251, WO 2009/080252, WO 2009/080253), electrostatically-matched Fc-heterodimeric molecules (Amgen, EP1870459 and WO2009089004; Chugai, US201000155133; Oncomed, WO2010129304), LUZ-Y (Genentech), DIG- body, PIG-body and TIG-body (Pharmabcine), Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono, WO2007110205), Bispecific IgGl and lgG2 (Pfizer/Rinat, W011143545), Azymetric scaffold (Zymeworks/Merck, WO201205
- IgG-like dual targeting molecules include but are not limited to Dual Targeting (DT)-lg (GSK/Domantis), Two-in-one Antibody (Genentech), Cross-linked Mabs (Karmanos Cancer Center), mAb2 (F-Star, WO2008003116), ZybodiesTM (Zyngenia), approaches with common light chain (Crucell/Merus, US 7,262,028), K ⁇ Bodies (Novlmmune) and CovX-body (CovX/Pfizer).
- DT Dual Targeting
- GSK/Domantis Two-in-one Antibody
- Cross-linked Mabs Karmanos Cancer Center
- mAb2 F-Star, WO2008003116
- ZybodiesTM Zyngenia
- approaches with common light chain Crucell/Merus, US 7,262,028
- K ⁇ Bodies Novlmmune
- CovX-body CovX/Pfizer
- IgG fusion molecules include but are not limited to Dual Variable Domain
- Fc fusion molecules include but are not limited to ScFv/Fc Fusions
- Fab fusion bispecific antibodies include but are not limited to F(ab)2 (Medarex/AMGEN), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock ® (DNL) (ImmunoMedics), Bivalent Bispecific (Biotecnol) and Fab-Fv (UCB-Celltech).
- ScFv-, diabody-based and domain antibodies include but are not limited to Bispecific T Cell Engager (BiTE ® ) (Micromet, Tandem Diabody (TandabTM) (Affimed), Dual Affinity Retargeting Technology (DART) (MacroGenics), Single-chain Diabody (Academic), TCR-like Antibodies (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack) and COMBODY (Epigen Biotech), dual targeting nanobodies ® (Ablynx), dual targeting heavy chain only domain antibodies.
- a bispecific antibody for use as an ADC according the present invention may be generated by introducing modifications in the constant region of the antibody.
- the bispecific antibody comprises a first and a second heavy chain, each of the first and second heavy chain comprises at least a hinge region, a CH2 and CH3 region, wherein in the first heavy chain at least one of the amino acids in the positions corresponding to positions selected from the group consisting of K409, T366, L368, K370, D399, F405, and Y407 in a human IgGl heavy chain has been substituted, and in the second heavy chain at least one of the amino acids in the positions corresponding to a position selected from the group consisting of F405, T366, L368, K370, D399, Y407, and K409 in a human IgGl heavy chain has been substituted, and wherein the first and the second heavy chains are not substituted in the same positions.
- the amino acid in the position corresponding to K409 in a human IgGl heavy chain is not K, L or M and optionally the amino acid in the position corresponding to F405 in a human IgGl heavy chain is F
- the amino acid in the position corresponding to F405 in a human IgGl heavy chain is not F and the amino acid in the position corresponding to K409 in a human IgGl heavy chain is K.
- the amino acid in the position corresponding to F405 in a human IgGl heavy chain is not F, , and G
- the amino acids in the positions corresponding to a position selected from the group consisting of; T366, L368, K370, D399, Y407, and K409 in a human IgGl heavy chain has been substituted.
- amino acid in position corresponding to K409 in a human is amino acid in position corresponding to K409 in a human
- IgGl heavy chain is another than K, L or M in the first heavy chain, and in the second heavy chain the amino acid in position corresponding to F405 in a human IgGl heavy chain is not F and optionally the amino acid in the position corresponding to K409 in a human IgGl heavy chain is K.
- the amino acid in the position corresponding to F405 in a human IgGl heavy chain is L in said first heavy chain, and the amino acid in the position corresponding to K409 in a human IgGl heavy chain is R in said second heavy chain, or vice versa.
- the amino acid in the position corresponding to K409 in a human IgGl heavy chain is R in the first heavy chain
- the amino acid in the position corresponding to F405 in a human IgGl heavy chain is L in the second heavy chain.
- amino acids of the constant region sequences are herein numbered according to the Eu-index of numbering (described in Kabat, 1991).
- the terms "Eu-index of numbering” and “Eu numbering as set forth in Kabat” may be used interchangeably and have the same meaning and purpose.
- an amino acid or segment in one sequence that "corresponds to" an amino acid or segment in another sequence is one that aligns with the other amino acid or segment using a standard sequence alignment program such as ALIGN, ClustalW or similar, typically at default settings and has at least 50%, at least 80%, at least 90%, or at least 95% identity to a human IgGl heavy chain. It is well-known in the art how to align a sequence or segment in a sequence and thereby determine the corresponding position in a sequence to an amino acid position according to the present invention.
- amino acid corresponding to position refers to an amino acid position number in a human IgGl heavy chain.
- amino acid and “amino acid residue” may herein be used interchangeably, and are not to be understood limiting.
- amino acid may be defined by conservative or non-conservative amino acids, and may therefore be classified accordingly.
- Amino acid residues may also be divided into classes defined by alternative physical and functional properties. Thus, classes of amino acids may be reflected in one or both of the following lists:
- Non-polar Uncharged Residues C, M, and P
- Aromatic Residues F, Y, and W
- Residues involved in turn formation A, C, D, E, G, H, K, N, Q, R, S, P, and T
- Xaa or X may typically represent any of the 20 naturally occurring amino acids.
- naturally occurring refers to any one of the following amino acid residues; glycine, alanine, valine, leucine, isoleucine, serine, threonine, lysine, arginine, histidine, aspartic acid, asparagine, glutamic acid, glutamine, proline, tryptophan, phenylalanine, tyrosine, methionine, and cysteine.
- K409R or “Lys409Arg” means, that the antibody comprises a substitution of Lysine with Arginine in amino acid position 409.
- the original amino acid(s) and/or substituted amino acid(s) may comprise more than one, but not all amino acid(s), the more than one amino acid may be separated by ",” or "/”.
- the substitution of Lysine with Arginine, Alanine, or Phenylalanine in position 409 is:
- a substitution embraces a substitution into any one or the other nineteen natural amino acids, or into other amino acids, such as non-natural amino acids.
- a substitution of amino acid K in position 409 includes each of the following substitutions: 409A, 409C, 409D, 409E, 409F, 409G, 409H, 409I, 409L, 409M, 409N, 409Q, 409R, 409S, 409T, 409V, 409W, 409P, and 409Y.
- This is, by the way, equivalent to the designation 409X, wherein the X designates any amino acid other than the original amino acid.
- substitutions may also be designated K409A, K409C, etc. or K409A,C, etc. or K409A/C/etc. The same applies by analogy to each and every position mentioned herein, to specifically include herein any one of such substitutions.
- the antibody according to the invention may also comprise a deletion of an amino acid residue.
- Such deletion may be denoted “del”, and includes, e.g., writing as K409del.
- the Lysine in position 409 has been deleted from the amino acid sequence.
- both the first and the second binding region of the bispecific antibody bind AXL.
- the first binding region comprises a different set of CDR sequences than the second binding region.
- the bispecific antibody comprising a first and a second binding region, and a first and a second heavy chain, wherein the first and the second binding regions each comprise a VH and VL region selected from the group consisting of;
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 36, 37, and 38, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively, [107]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively, and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively [733];
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 36, 37, and 38, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively, [107]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 55, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 55, GAS, and 56, respectively. [154];
- first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 36, 37, and 38, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively, [107]; and a second VH region comprising the
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 36, 37, and 38, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively, [107]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 62, 63, and 64, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 65, GAS, and 66, respectively, [172];
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 36, 37, and 38, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively, [107]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 67, 68, and 69, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 70, GAS, and 71, respectively, [181];
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 36, 37, and 38, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively, [107]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 73, and 75, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 76, ATS, and 77, respectively, [183];
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 36, 37, and 38, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively, [107]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 74, and 75, respectively; and a second
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 76, ATS, and 77, respectively, [183-N52Q]; k) a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.
- VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 36, 37, and 38, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively, [107]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 83, 84, and 85, respectively; and a second
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 86, GAS, and 87, respectively, [608-01];
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 36, 37, and 38, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 39, GAS, and 40, respectively, [107]; and a second VH region comprising the
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ I D Nos.: 44, AAS, and 45, respectively, [107];
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 60, GAS, and 61, respectively, [171];
- cc a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 46, 47, and 48, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 49, AAS, and 50, respectively, [148]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 83, 84, and 85, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 86, GAS, and 87, respectively, [608-01];
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 46, 47, and 48, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 49, AAS, and 50, respectively, [148]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 88, 89, and 90, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 91, GAS, and 92, respectively, [610-01];
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 46, 47, and 48, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ I D Nos. : 49, AAS, and 50, respectively, [148]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 94, 95, and 95, respectively; and a second
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 96, GAS, and 97, respectively, [613];
- hh a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 49, AAS, and 50, respectively, [148]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 110, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 112, AAS, and 113, respectively, [726];
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 49, AAS, and 50, respectively, [148]; and a second VH region comprising the
- jj a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 41, 42, and 43, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 44, AAS, and 45, respectively, [140];
- kk a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 55, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 55, GAS, and 56, respectively. [154];
- first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 54, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 55, GAS, and 56, respectively. [154-M103L];
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 57, 58, and 59, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 60, GAS, and 61, respectively, [171];
- nn a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 62, 63, and 64, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 65, GAS, and 66, respectively, [172];
- a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 67, 68, and 69, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 70, GAS, and 71, respectively, [181];
- ss a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ I D Nos. : 114, 115, and 116, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 83, 84, and 85, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 86, GAS, and 87, respectively, [608-01];
- tt a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ I D Nos. : 114, 115, and 116, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 88, 89, and 90, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos. : 91, GAS, and 92, respectively, [610-01];
- vv a first VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively; and a first VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733];and a second VH region comprising the CDRl, CDR2, and CDR3 sequences of SEQ I D Nos.: 98, 99, and 100, respectively; and a second VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 101, DAS, and 102, respectively, [613-08];
- VL region comprising the CDRl, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CD 1, CDR2, and CDR3 sequences of SEQ ID Nos.: 103, 104, and 105, respectively; and a second VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 106, GAS, and 107, respectively, [620-06];
- a first VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively; and a first VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 110, respectively; and a second VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 112, AAS, and 113, respectively, [726]; and
- yy a first VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively; and a first VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 117, DAS, and 118, respectively, [733]; and a second VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 111, respectively; and a second VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 112, AAS, and 113, respectively, [726-M101L];
- Antibodies conjugated to a cytotoxic agent, drug or the like are also known as antibody-drug conjugates (ADC).
- ADC antibody-drug conjugates
- An ADC may have a half-life of sufficient periods of time for the antibody-drug conjugate to be internalized, degraded and induce cell killing by the released toxin.
- an ADC can comprise an anti-AXL antibody or bispecific antibody and a therapeutic moiety, such as a cytotoxic agent, a chemotherapeutic drug, or the like.
- a therapeutic moiety such as a cytotoxic agent, a chemotherapeutic drug, or the like.
- the cytotoxic agent, chemotherapeutic drug or the like may be conjugated to the antibody or the bispecific antibody via a linker.
- ADCs are often designed such that the cytotoxic payload is inactive when conjugated to the antibody.
- the cytotoxic payload may be released intracellularly upon internalization of the ADC after binding to the plasma-membrane of cells, or alternatively in response to proteolytic activity in the tumor microenvironment.
- the term "internalized” or “internalization” as used herein, refers to a biological process in which molecules such as the AXL-ADC are engulfed by the cell membrane and drawn into the interior of the cell. It may also be referred to as "endocytosis".
- antibodies which undergo internalization may be suited for conjugation to a cytotoxic agent, drug, or the like, optionally via a linker, which is designed to be cleaved intracellularly.
- the ADC Once internalized, the ADC may be delivered to lysosomes in most cases, where effective drug release takes advantage of the catabolic environment found with these organelles. It is typically a linker that connects the antibody with a cytotoxic agent.
- linkers have been designed to be cleaved only in a specific microenvironment found in or on the target tumor cell or in the tumor microenvironment. Examples include linkers that are cleaved by acidic conditions, reducing conditions, or specific proteases.
- Stability of the antibody-linker-drug in circulation is important because this allows antibody-mediated delivery of the drug to specific target cells.
- the long circulating half- life of the ADC provides exposure for several days to weeks post injection.
- Drugs that are conjugated through non-cleavable linkers and protease-cleavable linkers are generally more stable in circulation than disulfide and hydrazone linkers, although the stability of the latter two linkers can be tuned by altering the neighboring chemical structure (Alley et al., 2010).
- the therapeutic moiety is a cytotoxic agent.
- a cytotoxin or cytotoxic agent includes any agent that is detrimental to (e.g., kills) cells.
- Suitable cytotoxic agents for forming ADCs for use in the present invention include taxol, tubulysins, duostatins, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, maytansine or an analog or derivative thereof, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin; calicheamicin or analogs or derivatives thereof; antimetabolites (such as met
- rachelmycin or analogs or derivatives of CC-1065
- dolastatin auristatin
- antibiotics such as dactinomycin (formerly actinomycin), bleomycin, daunorubicin (formerly daunomycin), doxorubicin, idarubicin, mithramycin, mitomycin, mitoxantrone, plicamycin, anthramycin (AMC)
- anti-mitotic agents e.g., tubulin-targeting agents
- diphtheria toxin and related molecules such as diphtheria A chain and active fragments thereof and hybrid molecules
- ricin toxin such as ricin A or a deglycosylated ricin A chain toxin
- cholera toxin a Shiga-like tox
- conjugated molecules include antimicrobial/lytic peptides such as CLIP, Magainin 2, mellitin, Cecropin, and P18; ribonuclease ( Nase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, diphtherin toxin, and Pseudomonas endotoxin. See, for example, Pastan et al., Cell 47, 641 (1986) and Goldenberg, Calif. A Cancer Journal for Clinicians 44, 43 (1994).
- Therapeutic agents that may be administered in combination with anti-AXL antibodies or antibody-drug conjugates for use according to the present invention as described elsewhere herein, such as, e.g., anti-cancer cytokines or chemokines, are also candidates for therapeutic moieties useful for conjugation to an antibody for use according to the present invention.
- cytotoxic agent refers to any agent that is detrimental to (e.g., kills) cells.
- cytotoxic agent refers to any agent that is detrimental to (e.g., kills) cells.
- the cytotoxic agent is linked to said antibody, or fragment thereof, with a cleavable linker, such as /V-succinimydyl 4-(2-pyridyldithio)-pentanoate (SSP), maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB) or AV-1 K-lock valine- citrulline.
- a cleavable linker such as /V-succinimydyl 4-(2-pyridyldithio)-pentanoate (SSP), maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB) or AV-1 K-lock valine- citrulline.
- cleavable linker refers to a subset of linkers that are catalyzed by specific proteases in the targeted cell or in the tumor microenvironment, resulting in release of the cytotoxic agent.
- Examples of cleavable linkers are linkers based on chemical motifs including disulfides, hydrazones or peptides.
- Another subset of cleavable linker adds an extra linker motif between the cytotoxic agent and the primary linker, i.e. the site that attaches the linker-drug combination to the antibody.
- the extra linker motif is cleavable by a cleavable agent that is present in the intracellular environment (e. g.
- the linker can be, e. g. a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including but not limited to, a lysosomal or endosomal protease.
- the peptidyl linker is at least two amino acids long or at least three amino acids long.
- Cleaving agents can include cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives resulting in the release of active drug inside the target cells (see e. g. Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123).
- the peptidyl linker cleavable by an intracellular protease is a Val-Cit (valine-citrulline) linker or a Phe-Lys (phenylalanine-lysine) linker (see e.g. US6214345, which describes the synthesis of doxorubicin with the Val-Cit linker).
- Val-Cit valine-citrulline
- Phe-Lys phenylalanine-lysine linker
- the cytotoxic agent is linked to said antibody, or fragment thereof, with a non-cleavable linker, such as succinimidyl-4(/V-maleimidomethyl)cyclohexane-l- carboxylate (MCC) or maleimidocaproyl (MC).
- a non-cleavable linker such as succinimidyl-4(/V-maleimidomethyl)cyclohexane-l- carboxylate (MCC) or maleimidocaproyl (MC).
- noncleavable linker refers to a subset of linkers which, in contrast to cleavable linkers, do not comprise motifs that are specifically and predictably recognized by intracellular or extracellular proteases.
- ADCs based on non-cleavable linkers are not released or cleaved form the antibody until the complete antibody-linker-drug complex is degraded in the lysosomal compartment.
- examples of a non-cleavable linker are thioethers.
- the linker unit is not cleavable and the drug is released by antibody degradation (see US 2005/0238649). Typically, such a linker is not substantially sensitive to the extracellular environment.
- linker not substantially sensitive to the extracellular environment in the context of a linker means that no more than 20%, typically no more than about 15%, more typically no more than about 10%, and even more typically no more than about 5%, no more than about 3%, or no more than about 1% of the linkers, in a sample of antibody drug conjugate compound, are cleaved when the antibody drug conjugate compound is present in an extracellular environment [e.g. plasma). Whether a linker is not substantially sensitive to the extracellular environment can be determined for example by incubating with plasma the antibody drug conjugate compound for a predetermined time period [e.g. 2, 4, 8, 16 or 24 hours) and then quantitating the amount of free drug present in the plasma.
- a predetermined time period e.g. 2, 4, 8, 16 or 24 hours
- cytotoxic agent is selected from the group: DNA-targeting agents, e.g. DNA alkylators and cross-linkers, such as calicheamicin, duocarmycin, rachelmycin (CC- 1065), pyrrolo[2,l-c] [l,4] benzodiazepines (PBDs), and indolinobenzodiazepine (IGN); microtubule- targeting agents, such as duostatin, such as duostatin-3, auristatin, such as monomethylauristatin E (MMAE) and monomethylauristatin F (M MAF), dolastatin, maytansine, /V(2')-deacetyl-/V(2')-(3- marcapto-l-oxopropyl)-maytansine (DM1), and tubulysin; and nucleoside analogs; or an analogs, derivatives, or prodrugs thereof.
- DNA-targeting agents e.g. DNA alkylators and
- the AXL-ADC comprises a combination of; i) a cleavable linker and a cytotoxic agent having bystander kill capacity;
- bystander cytotoxicity refers to the effect where the cytotoxic agent that is conjugated to the antibody by either a cleavable or non-cleavable linker has the capacity to diffuse across cell membranes after the release from the antibody and thereby cause killing of neighboring cells.
- the cytotoxic agent when conjugated by a cleavable or non-cleavable linker, it may be either the cytotoxic agent only or the cytotoxic agent with a part of the linker that has the bystander kill capacity.
- the capacity to diffuse across cell membranes is related to the hydrophobicity of the the cytotoxic agent or the combination of the cytotoxic agent and the linker.
- Such cytotoxic agents may advantageously be membrane-permeable toxins, such as MMAE that has been released from the antibody by proteases. Especially in tumors with heterogeneous target expression and in solid tumors where antibody penetration may be limited, a bystander killing effect may be desirable.
- no bystander kill capacity refers to the effect where the cytotoxic agent that is conjugated to the antibody by either a cleavable or non-cleavable linker does not have the capacity to diffuse across cell membranes after release from the antibody.
- cytotoxic agents or combinations of the cytotoxic agent with the linker will not be able to kill neighboring cells upon release from the antibody. It is believed without being bound by theory, that such combinations of a cytotoxic agent and either a cleavable or non-cleavable linker will only kill cells expressing the target that the antibody binds.
- a stable link between the antibody and cytotoxic agent is an important factor of an ADC.
- Both cleavable and non-cleavable types of linkers have been proven to be safe in preclinical and clinical trials.
- the cytotoxic agent is chosen from the group of microtubule targeting agents, such as auristatins and maytansinoids.
- microtubule-targeting agent refers to an agent or drug which inhibits mitosis (cell division).
- Microtubules are structures that are essential for proper separation of DNA during cell division, and microtubule function critically depends on 'dynamic instability', i.e. the process in which microtubule structures are continuously elongated and shortened.
- Microtubule-targeting agents disrupt or stabilize microtubules, which prevents formation of the mitotic spindle, resulting in mitotic arrest and apoptosis.
- the microtubule-targeting agents can be derived from e.g.
- microtubule-targeting agents are paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, duostatins, auristatins, maytansanoids, tubulysins, and dolastatin.
- the cytotoxic agent is auristatins or auristatin peptide analogs and derivates (US 5,635,483;US 5,780,588).
- Auristatins have been shown to interfere with microtubule dynamics, GTP hydrolysis and nuclear and cellular division (Woyke et al., 2001) and have anti-cancer (US 5,663,149) and anti-fungal activity (Pettit, 1998).
- the auristatin drug moiety may be attached to the antibody via a linker, through the N (amino) terminus or the C (terminus) of the peptidic drug moiety.
- Exemplary auristatin embodiments include the N-terminus-linked monomethyl auristatin drug moieties D E and D F , disclosed in Senter et al. (2004) and described in US 2005/0238649.
- the cytotoxic agent is monomethyl auristatin E (MMAE); wherein the antibody is linked to MMAE at the nitrogen (N) on the left-hand side of the chemical structure above by the appropriate linker.
- MMAE monomethyl auristatin E
- the cytotoxic agent monomethyl auristatin E is linked to the antibody via a valine-citrulline (VC) linker.
- cytotoxic agent monomethyl auristatin E is linked to the antibody via a valine-citrulline (VC) linker and the maleimidocaproyl (MC)linker, wherein the combination of the cytotoxic agent and the linkers has the chemical structure;
- MAb is the antibody
- the cytotoxic agent is monomethyl auristatin F (M MAF);
- the cytotoxic agent monomethyl auristatin F is linked to the antibody via a maleimidocaproyi (mc)-linker, wherein the combination of the cytotoxic agent and linker has the chemical structure;
- MAb is the antibody
- the cytotoxic agent is duostatin3.
- the cytotoxic agent is a DNA-targeting agent.
- DNA-targeting agent refers to a specific class of cytotoxic agents which are able to alkylate and/or cross-link DNA.
- IGN agents comprising indolino-benzodiazepinedimers and pyrrolo[2,l-c] [1,4] benzodiazepines (PBDs) which are highly potent by virtue of their ability to alkylate and cross-link DNA.
- PBDs pyrrolo[2,l-c] [1,4] benzodiazepines
- IGN agents comprising indolino-benzodiazepinemonomers which are highly potent by virtue of the ability to alkylate only DNA.
- Duocarmycins are another class of DNA-acting agents. Duocarmycins are small-molecule, synthetic DNA minor groove binding alkylating agents. These compounds are suitable to target solid tumors as well as hematological tumors.
- the AXL-ADC comprises two to four cytotoxic molecules per antibody.
- two to four cytotoxic molecules per antibody may be superior to more heavily loaded conjugates that are cleared more rapidly from the circulation than less loaded conjugates.
- the cytotoxic agent loading is represented by p and is the average number of cytotoxic agent moieties per antibody in a molecule (also designated as the drug to antibody ratio, DA ).
- the cytotoxic agent loading may range from 1 to 20 drug moieties per antibody and may occur on amino acids with useful functional groups such as, but not limited to, amino or sulfhydryl groups, as in lysine or cysteine.
- the number of cytotoxic agents per antibody is from 1 to 8, such as 2 to 7, such as 2 to 6, such as 2 to 5, such as 2 to 4, and such as 2 to 3.
- the AXL-ADC comprises four to eight cytotoxic molecules per antibody. In another embodiment, the AXL-ADC comprises six to ten cytotoxic molecules per antibody. In yet another embodiment, the AXL-ADC comprises 10 to 30, such as 15 to 25, such as 20, cytotoxic molecules per antibody.
- p may be limited by the number of attachment sites on the antibody, for example where the attachment is a cysteine thiol or a lysine.
- the attachment is a cysteine thiol or a lysine.
- antibodies do not contain many free and reactive cysteine thiol groups which may be linked to a drug moiety as most cysteine thiol residues in antibodies exist as disulfide bridges. Therefore, in those embodiments, where the cytotoxic agent is conjugated via a cysteine thiol, the antibody may be reduced with reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP), under partial or fully reducing conditions, to generate reactive cysteine thiol groups.
- DTT dithiothreitol
- TCEP tricarbonylethylphosphine
- the drug loading for an ADC of the invention ranges from 1 to about 8, as a maximum of 8 free cysteine thiol groups becomes available after (partial) reduction of the antibody (there are 8 cysteines involved in inter-chain disulfide bonding).
- the drug linker moiety is vcMMAE.
- the vcMMAE drug linker moiety and conjugation methods are disclosed in WO 2004/010957; US 7,659,241; US 7,829,531; and US 7,851,437 (Seattle Genetics; each of which incorporated herein by reference).
- vcMMAE is formed by conjugation of the linker mc-vc-PAB and the cytotoxic moiety MMAE, and the vcMMAE drug linker moiety is bound to the anti-AXL antibodies at the cysteine residues using a method similar to those disclosed therein, e.g., as described in Example 8.
- the drug linker moiety is mcMMAF.
- the mcMMAF drug linker moiety and conjugation methods are disclosed in US 7,498,298; US 7,994,135 and WO 2005/081711 (Seattle Genetics; each of which incorporated herein by reference), and the mcMMAF drug linker moiety is bound to the anti-AXL antibodies at the cysteine residues using a method similar to those disclosed therein.
- the cytotoxic agent is linked to 1 or 2 lysines within the antibody amino acid sequence by K-LockTM conjugation as described in WO 2013/173391, WO 2013/173392 and WO 2013/173393 (Concortis Biosystems).
- Duostatin3 also known as Duo3 may also be bound to the anti-AXL antibodies at the lysine residues using a method similar to those described therein.
- Other linker technologies may be used in the anti-AXL antibody drug conjugates for the use of the invention, such as linkers comprising a hydroxyl group.
- the linker is attached to free cysteine residues of the anti-AXL antibody obtained by (partial) reduction of the anti-AXL antibody.
- the linker is mc-vc-PAB and the cytotoxic agent is MMAE; or the linker SSP and the cytotoxic agent is DM1.
- the linker is MMC and the cytotoxic agent is DM1; or the linker is MC and the cytotoxic agent is MMAF.
- the linker is the cleavable linker AV1-K lock and the cytotoxic agent is duostatin3.
- the AXL-ADC comprises the linker mc-vc-PAB, the cytotoxic agent MMAE and an antibody wherein the at least one binding region comprises a VH region and a VL region selected from the group consisting of;
- the antibody comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of:
- VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:55, GAS, and 56, respectively [154];
- (cc) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:55, GAS, and 56, respectively [154-M103 L] ;
- VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:62, 63, and 64, respectively; and a VL region comprising the CDR1, CDR2, and
- VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ I D Nos.:81 , A AS, and 82, respectively, [187] ;
- VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:96, GAS, and 97, respectively, [613];
- VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos. : 98, 99, and 100, respectively; and a VL region com prising the CDR1 , CDR2, and CDR3 sequences of SEQ I D Nos.: 101 , DAS, and 102, respectively, [613-08] ;
- (tt) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:123, 124, and 125, respectively; and a VL region comprising CDR1, CDR2, and CDR3 sequences of SEQ I D Nos.:60, GAS, and 61 , respectively [171 / 172 / 181]; and
- Vv a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:93, 126, and 127, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.:96, GAS, and 97, respectively [613 / 608-01 /
- an anti-AXL antibody drug conjugate comprises a conjugated nucleic acid or nucleic acid-associated molecule.
- the conjugated nucleic acid is a cytotoxic ribonuclease, an antisense nucleic acid, an inhibitory RNA molecule (e.g., a siRNA molecule) or an immunostimulatory nucleic acid (e.g., an immunostimulatory CpG motif-containing DNA molecule).
- an anti-AXL antibody is conjugated to an aptamer or a ribozyme or a functional peptide analog or derivate thereof.
- anti-AXL antibody drug conjugates comprising one or more radiolabeled amino acids are provided.
- a radiolabeled anti-AXL antibody may be used for both diagnostic and therapeutic purposes (conjugation to radiolabeled molecules is another possible feature).
- labels for polypeptides include 3 H, 14 C, 15 N, 35 S, 90 Y, 99 Tc, and 125 ⁇ , 131 l, and 186 Re.
- Methods for preparing radiolabeled amino acids and related peptide derivatives are known in the art (see for instance Junghans et al. (1996); US 4,681,581; US 4,735,210; US 5,101,827; US 5,102,990; US 5,648,471; and US 5,697,902.
- a halogen radioisotope may be conjugated by a chloramine T method.
- the antibody is conjugated to a radioisotope or to a radioisotope-containing chelate.
- the antibody can be conjugated to a chelator linker, e.g. DOTA, DTPA or tiuxetan, which allows for the antibody to be complexed with a radioisotope.
- the antibody may also or alternatively comprise or be conjugated to one or more radiolabeled amino acids or other radiolabeled molecules.
- a radiolabeled anti-AXL antibody may be used for both diagnostic and therapeutic purposes.
- Non-limiting examples of radioisotopes include 3 H, 14 C, 15 N, 35 S, 90 Y, "Tc, 125 l, m ln, 131 l, 186 e, 213 Bs, 225 Ac and 227 Th.
- Anti-AXL antibodies may also be chemically modified by covalent conjugation to a polymer to for instance increase their circulating half-life.
- exemplary polymers, and methods to attach them to peptides are illustrated in for instance US 4,766,106; US 4,179,337; US 4,495,285 and US 4,609,546.
- Additional polymers include polyoxyethylated polyols and polyethylene glycol (PEG) (e.g., a PEG with a molecular weight of between about 1,000 and about 40,000, such as between about 2,000 and about 20,000). This may for example be used if the anti-AXL antibody is a fragment.
- PEG polyethylene glycol
- any method known in the art for conjugating the anti-AXL antibody to the conjugated molecule(s), such as those described above, may be employed, including the methods described by Hunter et al. (1974), Pain et al. (1981) and Nygren (1982).
- Such antibodies may be produced by chemically conjugating the other moiety to the N-terminal side or C-terminal side of the anti-AXL antibody (e.g., an anti-AXL antibody H or L chain) (see, e.g., Kanemitsu, 1994).
- conjugated antibody derivatives may also be generated by conjugation at internal residues or sugars, or non- naturally occurring amino acids or additional amino acids that have been introduced into the antibody constant domain, where appropriate.
- the agents may be coupled either directly or indirectly to an anti-AXL antibody.
- One example of indirect coupling of a second agent is coupling via a spacer moiety to cysteine or lysine residues in the antibody.
- an anti-AXL antibody is conjugated, via a spacer or linker, to a prodrug molecule that can be activated in vivo to a therapeutic drug. After administration, the spacers or linkers are cleaved by tumor cell-associated enzymes or other tumor- specific conditions, by which the active drug is formed.
- pro-drug technologies and linkers are described in WO 2002/083180, WO 2004/043493, WO 2007/018431, WO 2007/089149, WO 2009/017394 and WO 2010/62171 (Syngenta BV; each of which incorporated herein by reference).
- Suitable antibody-pro-drug technology and duocarmycin analogs can also be found in US 6,989,452 (Medarex; incorporated herein by reference).
- the anti-AXL antibody is attached to a chelator linker, e.g. tiuxetan, which allows for the antibody to be conjugated to a radioisotope.
- a chelator linker e.g. tiuxetan
- the AXL-ADC for use according to the present invention can be administered in the form of a composition.
- the composition is a pharmaceutical composition comprising the AXL-ADC and a pharmaceutical carrier.
- the AXL-ADC or pharmaceutical composition comprising the AXL-
- ADC is for use in treating a neoplasm in combination with the at least one therapeutic agent with which the neoplasm is being or has been treated, i.e., the chemotherapeutic agent, tyrosine kinase inhibitor, PI3K inhibitor, mAb/rTKI and/or serine/threonine kinase inhibitor according to any preceding aspect or embodiment.
- the therapeutic agent may be a chemotherapeutic agent, a TKI or a S/Th TKI according to any preceding aspect or embodiment.
- the AXL-ADC and the therapeutic agent are separately administered.
- the pharmaceutical composition comprising the AXL- ADC further comprises the at least one therapeutic agent with which the neoplasm is being or has been treated, i.e., the chemotherapeutic agent, tyrosine kinase inhibitor, PI3K inhibitor, mAb/rTKI and/or serine/threonine kinase inhibitor according to any preceding aspect or embodiment.
- the therapeutic agent may be a chemotherapeutic agent, a TKI or a S/Th TKI according to any preceding aspect or embodiment.
- the AXL-ADCs for use according to the present invention in combination with the at least one therapeutic agent can be also be provided in the form of a kit, for simultaneous, separate or sequential administration, wherein the kit may further comprise instructions for use.
- the ADC and the at least one therapeutic agent are typically formulated as separate pharmaceutical compositions.
- the tyrosine kinase inhibitor in the combination, composition or kit is an EGF antagonist.
- the tyrosine kinase inhibitor in the combination, composition or kit is selected from the group consisting of erlotinib, gefitinib, lapatinib, imatinib, sunitinib, crizotinib, midostaurin (PKC412) and quizartinib (AC220), such as , e.g., erlotinib or an analog or derivative thereof such as lapatinib, gefitinib or.
- the tyrosine kinase inhibitor is erlotinib.
- the serine/threonine kinase inhibitor in the combination, composition or kit is selected from vemurafenib, dabrafenib, selumetinib (AZD6244), VTX11E, trametinib and PLX4720.
- the BRAF inhibitor in the combination, composition or kit is vemurafenib (PLX4032) or a therapeutically effective analog or derivative thereof, such as dabrafenib or PLX4720.
- the BRAF inhibitor is vemurafenib.
- the BRAF-inhibitor is dabrafenib.
- the serine/threonine kinase inhibitor in the combination, composition or kit comprises at least one BRAF-inhibitor and at least one MEK-inhibitor, wherein the at least one BRAF-inhibitor is selected from vemurafenib, dabrafenib and a combination thereof, and wherein the MEK-inhibitor is selected from selumetinib (AZD6244) and trametinib, and a combination thereof.
- the combination, composition or kit may comprise dabrafenib and trametinib; vemurafenib and trametinib; dabrafenib, vemurafenib and trametinib; dabrafenib and selumetinib; or vemurafenib and selumetinib.
- the at least one chemotherapeutic agent in the combination, composition or kit is a taxane, for example selected from paclitaxel and docetaxel.
- the at least one chemotherapeutic agent in the combination, composition or kit is selected from the group consisting of cisplatin, carboplatin, doxorubicin, etoposide and metformin.
- the PI3K inhibitor in the combination, composition or kit is alpelisib (BYL719).
- the mAb/rTKiin the combination, composition or kit is Cetuximab or MAB391.
- kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
- kit components such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
- Printed instructions either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
- compositions may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy (1995).
- the pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients should be suitable for the AXL-ADC and the chosen mode of administration. Suitability for carriers and other components of pharmaceutical compositions is determined based on the lack of significant negative impact on the desired biological properties of the chosen compound or pharmaceutical composition [e.g., less than a substantial impact (10% or less relative inhibition, 5% or less relative inhibition, etc.) upon antigen binding).
- a pharmaceutical composition may also include diluents, fillers, salts, buffers, detergents (e. g., a nonionic detergent, such as Tween-20 or Tween-80), stabilizers (e.g., sugars or protein-free amino acids), preservatives, tissue fixatives, solubilizers, and/or other materials suitable for inclusion in a pharmaceutical composition.
- detergents e. g., a nonionic detergent, such as Tween-20 or Tween-80
- stabilizers e.g., sugars or protein-free amino acids
- preservatives e.g., tissue fixatives, solubilizers, and/or other materials suitable for inclusion in a pharmaceutical composition.
- the actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
- the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
- the pharmaceutical composition may be administered by any suitable route and mode. Suitable routes of administering a compound of the present invention in vivo and in vitro are well known in the art and may be selected by those of ordinary skill in the art.
- the pharmaceutical composition is administered parenterally.
- parenteral administration and “administered parenterally” as used herein refers to modes of administration other than enteral and topical administration, usually by injection, and include epidermal, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injection and infusion.
- the pharmaceutical composition is administered by intravenous or subcutaneous injection or infusion.
- Pharmaceutically acceptable carriers include any and all suitable solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents, antioxidants and absorption- delaying agents, and the like that are physiologically compatible with an AXL-ADC or therapeutic agent for the use according to the present invention.
- aqueous and non-aqueous carriers examples include water, saline, phosphate-buffered saline, ethanol, dextrose, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, corn oil, peanut oil, cottonseed oil, and sesame oil, carboxymethyl cellulose colloidal solutions, tragacanth gum and injectable organic esters, such as ethyl oleate, and/or various buffers.
- Other carriers are well known in the pharmaceutical arts.
- Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions is contemplated.
- Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
- compositions may also comprise pharmaceutically acceptable antioxidants for instance (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
- water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
- oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytolu
- compositions may also comprise isotonicity agents, such as sugars, polyalcohols, such as mannitol, sorbitol, glycerol or sodium chloride in the compositions.
- isotonicity agents such as sugars, polyalcohols, such as mannitol, sorbitol, glycerol or sodium chloride in the compositions.
- the pharmaceutical compositions may also contain one or more adjuvants appropriate for the chosen route of administration such as preservatives, wetting agents, emulsifying agents, dispersing agents, preservatives or buffers, which may enhance the shelf life or effectiveness of the pharmaceutical composition.
- adjuvants appropriate for the chosen route of administration such as preservatives, wetting agents, emulsifying agents, dispersing agents, preservatives or buffers, which may enhance the shelf life or effectiveness of the pharmaceutical composition.
- the AXL-ADCs or therapeutic agents for the uses of the present invention may be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and micro-encapsulated delivery systems.
- Such carriers may include gelatin, glyceryl monostearate, glyceryl distearate, biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, poly-ortho-esters, and polylactic acid alone or with a wax, or other materials well known in the art. Methods for the preparation of such formulations are generally known to those skilled in the art. See e.g., obinbson: Sustained and Controlled Release Drug Delivery Systems (1978).
- the compounds may be formulated to ensure proper distribution in vivo.
- Pharmaceutically acceptable carriers for parenteral administration include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions is contemplated. Other active or therapeutic compounds may also be incorporated into the compositions.
- compositions for injection must typically be sterile and stable under the conditions of manufacture and storage.
- the composition may be formulated as a solution, micro-emulsion, liposome, or other ordered structure suitable to high drug concentration.
- the carrier may be an aqueous or a non-aqueous solvent or dispersion medium containing for instance water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
- the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- a coating such as lecithin
- surfactants it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as glycerol, mannitol, sorbitol, or sodium chloride in the composition.
- Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
- Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients e.g.
- dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients e.g. from those enumerated above.
- sterile powders for the preparation of sterile injectable solutions examples of methods of preparation are vacuum-drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
- dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
- examples of methods of preparation are vacuum-drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the antibodies for use as ADCs according to the invention can be prepared recombinantly in a host cell, using nucleic acid constructs, typically in the form of one or more expression vectors.
- the nucleic acid construct encodes one or more sequences set out in Table 1.
- the expression vector further comprises a nucleic acid sequence encoding the constant region of a light chain, a heavy chain or both light and heavy chains of an antibody, e.g. a human IgGl, ⁇ monoclonal antibody.
- the expressed anti-AXL antibody may subsequently be conjugated to a moiety as described herein.
- the anti-AXL antibody may subsequently be used to generate a bispecific antibody as described herein, before conjugation.
- the expression vector may be any suitable vector, including chromosomal, non- chromosomal, and synthetic nucleic acid vectors (a nucleic acid sequence comprising a suitable set of expression control elements).
- suitable vectors include derivatives of SV40, bacterial plasmids, phage DNA, baculovirus, yeast plasmids, vectors derived from combinations of plasmids and phage DNA, and viral nucleic acid (RNA or DNA) vectors.
- an anti-AXL antibody-encoding nucleic acid is comprised in a naked DNA or RNA vector, including, for example, a linear expression element (as described in for instance Sykes and Johnson (1997), a compacted nucleic acid vector (as described in for instance US 6,077,835 and/or WO 00/70087), a plasmid vector such as pBR322, pUC 19/18, or pUC 118/119, a "midge" minimally-sized nucleic acid vector (as described in for instance Schakowski et al.
- a linear expression element as described in for instance Sykes and Johnson (1997)
- a compacted nucleic acid vector as described in for instance US 6,077,835 and/or WO 00/70087
- a plasmid vector such as pBR322, pUC 19/18, or pUC 118/119
- a "midge" minimally-sized nucleic acid vector as described in for instance Schakowski et al
- nucleic acid vector construct such as a calcium phosphate-precipitated construct (as described in for instance WO 00/46147; Benvenisty and Reshef, 1986; Wigler et al., 1978; and Coraro and Pearson, 1981).
- nucleic acid vectors and the usage thereof are well known in the art (see for instance US 5,589,466 and US 5,973,972).
- the vector is suitable for expression of the anti-AXL antibody in a bacterial cell.
- examples of such vectors include expression vectors such as BlueScript (Stratagene), pIN vectors (Van Heeke and Schuster, 1989), pET vectors (Novagen, Madison Wl) and the like).
- An expression vector may also or alternatively be a vector suitable for expression in a yeast system. Any vector suitable for expression in a yeast system may be employed. Suitable vectors include, for example, vectors comprising constitutive or inducible promoters such as alpha factor, alcohol oxidase and PGH (reviewed in Ausubel et al., 1987, and Grant et al., 1987).
- a nucleic acid construct and/or vector may also comprise a nucleic acid sequence encoding a secretion/localization sequence, which can target a polypeptide, such as a nascent polypeptide chain, to the periplasmic space or into cell culture media.
- a secretion/localization sequence which can target a polypeptide, such as a nascent polypeptide chain, to the periplasmic space or into cell culture media.
- Such sequences are known in the art, and include secretion leader or signal peptides, organelle targeting sequences (e. g., nuclear localization sequences, E retention signals, mitochondrial transit sequences, chloroplast transit sequences), membrane localization/anchor sequences (e. g., stop transfer sequences, GPI anchor sequences), and the like.
- the anti-AXL antibody-encoding nucleic acids may comprise or be associated with any suitable promoter, enhancer, and other expression-facilitating elements.
- suitable promoter, enhancer, and other expression-facilitating elements include strong expression promoters (e.g., human CMV IE promoter/enhancer as well as RSV, SV40, SL3-3, MMTV, and HIV LTR promoters), effective poly (A) termination sequences, an origin of replication for plasmid product in E. coli, an antibiotic resistance gene as selectable marker, and/or a convenient cloning site (e.g., a polylinker).
- Nucleic acids may also comprise an inducible promoter as opposed to a constitutive promoter such as CMV IE (the skilled artisan will recognize that such terms are actually descriptors of a degree of gene expression under certain conditions).
- the anti-AXL-antibody-encoding expression vector may be positioned in and/or delivered to the host cell or host animal via a viral vector.
- the host cell can be a recombinant eukaryotic or prokaryotic host cell, such as a transfectoma, which produces an anti-AXL antibody as defined herein or a bispecific molecule of the invention as defined herein.
- host cells include yeast, bacterial and mammalian cells, such as CHO or HEK cells or derivatives thereof.
- the cell comprises a nucleic acid stably integrated into the cellular genome that comprises a sequence coding for expression of the anti-AXL antibody.
- the cell comprises a non-integrated nucleic acid, such as a plasmid, cosmid, phagemid, or linear expression element, which comprises a sequence coding for expression of the anti-AXL antibody.
- Recombinant host cell (or simply "host cell”), as used herein, is intended to refer to a cell into which an expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell, but also to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein.
- Recombinant host cells include, for example, transfectomas, such as CHO cells, HEK-293 cells, PER.C6, NSO cells, and lymphocytic cells, and prokaryotic cells such as E. coli and other eukaryotic hosts such as plant cells and fungi.
- transfectoma includes recombinant eukaryotic host cells expressing the antibody or a target antigen, such as CHO cells, PER.C6, NSO cells, HEK-293 cells, plant cells, or fungi, including yeast cells.
- the antibody may alternatively be produced from a hybridoma prepared from murine splenic B cells obtained from mice immunized with an antigen of interest, for instance in form of cells expressing the antigen on the surface, or a nucleic acid encoding an extracellular region of AXL.
- Monoclonal antibodies may also be obtained from hybridomas derived from antibody-expressing cells of immunized humans or non-human mammals such as rabbits, rats, dogs, primates, etc.
- Human antibodies may be generated using transgenic or transchromosomal mice, e.g. HuMAb mice, carrying parts of the human immune system rather than the mouse system.
- HuMAb mice contains a human immunoglobulin gene minilocus that encodes unrearranged human heavy ( ⁇ and ⁇ ) and ⁇ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous ⁇ and ⁇ chain loci (Lonberg et al., 1994a).
- mice mount a human antibody response upon immunization, the introduced human heavy and light chain transgenes, undergo class switching and somatic mutation to generate high affinity human lgG,K monoclonal antibodies (Lonberg et al., 1994b; Lonberg and Huszar, 1995; Harding and Lonberg, 1995).
- the preparation of HuMAb mice is described in detail in Taylor et al., 1992; Chen et al., 1993; Tuaillon et al., 1994; and Fishwild et al., 1996.
- human antibodies may be generated from transgenic mice or rats to produce human-rat chimeric antibodies that can be used as a source for the recombinant production of fully human monoclonal antibodies.
- human antibodies may be identified through display-type technologies, including, without limitation, phage display, retroviral display, ribosomal display, mammalian display, yeast display and other techniques known in the art, and the resulting molecules may be subjected to additional maturation, such as affinity maturation, as such techniques are well known in the art.
- VH CDR2 ISVSGGST 171 VH CD 3 AKEGYIWFGESLSYAFDI
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Abstract
Priority Applications (39)
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US15/742,818 US20180326084A1 (en) | 2015-07-10 | 2016-07-08 | Axl-specific antibody-drug conjugates for cancer treatment |
JP2018500605A JP6892431B2 (ja) | 2015-07-10 | 2016-07-08 | 癌治療用のaxl特異的抗体−薬物コンジュゲート |
CN201680052378.3A CN108368171A (zh) | 2015-07-10 | 2016-07-08 | 用于癌症治疗的axl特异性抗体-药物缀合物 |
DK16739079.8T DK3319993T3 (da) | 2015-07-10 | 2016-07-08 | AXL-SPECIFIKKE antistof-lægemiddelkonjugater til kræftbehandling |
LTEP16739079.8T LT3319993T (lt) | 2015-07-10 | 2016-07-08 | Axl specifiniai antikūno-vaistokonjugatai, skirti vėžiui gydyti |
RS20200419A RS60141B1 (sr) | 2015-07-10 | 2016-07-08 | Konjugati antitela specifičnog za axl i lekova za lečenje kancera |
MEP-2020-74A ME03772B (fr) | 2015-07-10 | 2016-07-08 | Conjugués anticorps-médicament spécifiques d'axl pour le traitement du cancer |
EA201890272A EA201890272A1 (ru) | 2015-07-10 | 2016-07-08 | Axl-специфические конъюгаты антитело-лекарственное средство для лечения рака |
EP20151844.6A EP3730520A1 (fr) | 2015-07-10 | 2016-07-08 | Conjugués anticorps-médicament spécifiques d'axl pour le traitement du cancer |
ES16739079T ES2784685T3 (es) | 2015-07-10 | 2016-07-08 | Productos conjugados de anticuerpo-fármaco específicos de AXL para el tratamiento del cáncer |
CA2991805A CA2991805A1 (fr) | 2015-07-10 | 2016-07-08 | Conjugues anticorps-medicament specifiques d'axl pour le traitement du cancer |
SI201630699T SI3319993T1 (sl) | 2015-07-10 | 2016-07-08 | AXL-specifični konjugati zdravila s protitelesom za zdravljenje raka |
AU2016292762A AU2016292762B2 (en) | 2015-07-10 | 2016-07-08 | AXL-specific antibody-drug conjugates for cancer treatment |
PL16739079T PL3319993T3 (pl) | 2015-07-10 | 2016-07-08 | Specyficzne wobec AXL koniugaty przeciwciało-lek do leczenia raka |
KR1020187004011A KR20180033523A (ko) | 2015-07-10 | 2016-07-08 | 암 치료를 위한 axl-특이적 항체-약물 접합체 |
EP16739079.8A EP3319993B1 (fr) | 2015-07-10 | 2016-07-08 | Conjugués anticorps-médicament spécifiques d'axl pour le traitement du cancer |
EA201891607A EA201891607A1 (ru) | 2016-01-13 | 2017-01-13 | Axl-специфичные конъюгаты антитело-лекарственное средство для лечения злокачественных новообразований |
JP2018536482A JP2019509257A (ja) | 2016-01-13 | 2017-01-13 | 癌治療用のaxl特異的抗体−薬物コンジュゲート |
EP17701812.4A EP3402822A1 (fr) | 2016-01-13 | 2017-01-13 | Conjugués anticorps-médicament spécifiques d'axl pour le traitement du cancer |
US16/069,395 US20190022243A1 (en) | 2016-01-13 | 2017-01-13 | Axl-specific antibody-drug conjugates for cancer treatment |
AU2017206967A AU2017206967B2 (en) | 2016-01-13 | 2017-01-13 | AXL-specific antibody-drug conjugates for cancer treatment |
PCT/EP2017/050718 WO2017121877A1 (fr) | 2016-01-13 | 2017-01-13 | Conjugués anticorps-médicament spécifiques d'axl pour le traitement du cancer |
CN201780017252.7A CN108884165A (zh) | 2016-01-13 | 2017-01-13 | 用于癌症治疗的axl特异性抗体药物缀合物 |
CN202310359872.6A CN116617410A (zh) | 2016-01-13 | 2017-01-13 | 用于癌症治疗的axl特异性抗体药物缀合物 |
CA3010887A CA3010887A1 (fr) | 2016-01-13 | 2017-01-13 | Conjugues anticorps-medicament specifiques d'axl pour le traitement du cancer |
US16/316,000 US20190233522A1 (en) | 2016-07-08 | 2017-07-07 | New dosage regimens for antibody drug conjugates based on anti-axl antibodies |
EP17742194.8A EP3481868A1 (fr) | 2016-07-08 | 2017-07-07 | Nouveaux régimes posologiques pour conjugués anticorps-médicaments à base d'anticorps anti-axl |
MA045625A MA45625A (fr) | 2016-07-08 | 2017-07-07 | Nouveaux régimes posologiques pour conjugués anticorps-médicaments à base d'anticorps anti-axl |
JP2019500471A JP2019524713A (ja) | 2016-07-08 | 2017-07-07 | 抗axl抗体に基づく抗体薬物コンジュゲートのための新しい投薬レジメン |
PCT/EP2017/067101 WO2018007592A1 (fr) | 2016-07-08 | 2017-07-07 | Nouveaux régimes posologiques pour conjugués anticorps-médicaments à base d'anticorps anti-axl |
IL256790A IL256790B (en) | 2015-07-10 | 2018-01-08 | Axl-specific antibody-drug conjugates for cancer treatment |
IL260065A IL260065A (en) | 2016-01-13 | 2018-06-17 | Conjugates of specific antibody-drug-axl for cancer treatment |
HK18114575.4A HK1255412A1 (zh) | 2015-07-10 | 2018-11-15 | 用於癌症治療的axl特異性抗體-藥物綴合物 |
HRP20200551TT HRP20200551T1 (hr) | 2015-07-10 | 2020-04-04 | Axl-specifični konjugati protutijelo-lijek za liječenje raka |
CY20201100339T CY1123983T1 (el) | 2015-07-10 | 2020-04-13 | Ειδικα σε axl συζευγματα αντισωματος-φαρμακου για τη θεραπεια καρκινου |
US16/891,796 US20200397913A1 (en) | 2015-07-10 | 2020-06-03 | Axl-specific antibody-drug conjugates for cancer treatment |
JP2021207104A JP2022037170A (ja) | 2016-01-13 | 2021-12-21 | 癌治療用のaxl特異的抗体-薬物コンジュゲート |
US17/957,302 US20230321261A1 (en) | 2016-01-13 | 2022-09-30 | Axl-specific antibody-drug conjugates for cancer treatment |
AU2022259847A AU2022259847C1 (en) | 2015-07-10 | 2022-10-28 | AXL-specific antibody-drug conjugates for cancer treatment |
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PCT/EP2015/065900 WO2016005593A1 (fr) | 2014-07-11 | 2015-07-10 | Anticorps se liant à axl |
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US201662278283P | 2016-01-13 | 2016-01-13 | |
US62/278,283 | 2016-01-13 |
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US16/891,796 Division US20200397913A1 (en) | 2015-07-10 | 2020-06-03 | Axl-specific antibody-drug conjugates for cancer treatment |
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EP (3) | EP3319993B1 (fr) |
JP (5) | JP6892431B2 (fr) |
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JP2021530436A (ja) * | 2018-05-15 | 2021-11-11 | フーダン ユニバーシティーFudan University | Axlを標的とする抗体および抗体−薬物複合体ならびにその製造方法と使用 |
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EP4149472A1 (fr) * | 2020-05-12 | 2023-03-22 | Novartis AG | Combinaisons thérapeutiques comprenant un inhibiteur de craf |
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